HGNC Approved Gene Symbol:BIRC5
Cytogenetic location:17q25.3 Genomic coordinates(GRCh38) :17:78,214,253-78,225,635 (from NCBI)
BIRC5 is an inhibitor of apoptosis (IAP), or programmed cell death, that is selectively overexpressed in common human cancers (Ambrosini et al., 1997).
Progression of the cell cycle and control of apoptosis are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. By hybridization screening of a human genomic library with an EPR1 (603411) probe,Ambrosini et al. (1997) isolated a cDNA encoding an inhibitor of apoptosis (IAP) protein, which they termed survivin. Survivin, also termed API4, encodes a deduced 142-amino acid protein. Sequence analysis revealed that survivin lacks a signal peptide and a hydrophobic domain for membrane insertion. Unlike other IAPs, survivin contains only 1 copy, rather than 2 or 3, of the baculovirus IAP repeat cys/his-based zinc finger, which is essential for apoptosis inhibition (see, e.g.,601712), and a C-terminal RING finger (e.g., RNF5602677). Survivin has 6 potential phosphorylation sites. Western blot analysis showed a 16.5-kD protein in transformed but not untransformed cell lines. By Northern blot analysis,Ambrosini et al. (1997) observed expression of a 1.9-kb transcript predominantly in fetal kidney and liver and to a lesser extent in fetal lung and brain. Expression was not observed in adult tissue except for thymus and placenta. Immunohistochemical and in situ hybridization analyses of tumor tissues revealed abundant expression in adenocarcinomas of lung, pancreas, breast, and prostate as well as in squamous lung cell carcinoma. Adjacent nonneoplastic tissue lacked survivin expression. Survivin is also expressed in high-grade but not low-grade non-Hodgkin lymphoma.
Adida et al. (1998) found high expression of survivin in multiple tissues in fetuses at least through week 21. Likewise, in the mouse, expression is detectable at embryonic day 11.5 but not after day embryonic day 14.
Using strand-specific probes for Northern blot analysis,Ambrosini et al. (1998) detected a prominent 1.3-kb transcript for EPR1, which is antisense to survivin on chromosome 17, in most adult and terminally differentiated human tissues examined. The 1.3-kb EPR1 transcript was also detected in all fetal tissues examined. In contrast, a major 1.9-kb transcript for survivin was detected only in transformed cell lines.
Independently,Zaman and Conway (2000) assayed the expression of EPR1 and survivin in human tissues with strand-specific probes. A survivin transcript of about 1.9 kb was detected in several tissues. Major EPR1 transcripts of 2.0, 1.6, and 1.0 kb were detected in various tissues depending on the probe used, with the 1.6-kb transcript present in all tissues.
Ambrosini et al. (1997) determined that the BIRC5 gene contains 4 exons.
Ambrosini et al. (1998) mapped the BIRC5 gene to chromosome 17q25 by pulsed field gel electrophoresis and single- and 2-color FISH. It is oriented in the opposite direction from EPR1 on the complementary strand.
By x-ray crystallography,Chantalat et al. (2000) determined the structure of the full-length human survivin to 2.7 angstroms. Strikingly, the structure forms a very unusual bow tie-shaped dimer. It does not dimerize through a C-terminal coiled coil, contrary to sequence analysis prediction. The C-terminal helices contain hydrophobic clusters with the potential for protein-protein interactions.Chantalat et al. (2000) concluded that the unusual shape and dimensions of survivin suggest that it serves an adaptor function through its alpha-helical extensions.
Muchmore et al. (2000) reported the crystal structure of survivin. In addition to a conserved N-terminal zinc finger baculovirus IAP repeat, survivin forms a dimer through a symmetric interaction with an intermolecularly bound zinc atom located along the molecular dyad axis. The interaction of the dimer-related C-terminal alpha helices forms an extended surface of approximately 70 angstroms in length. Mutagenesis analysis revealed that survivin dimerization and an extended negatively charged surface surrounding asp71 are required to counteract apoptosis and preserve ploidy.Muchmore et al. (2000) suggested that these findings may provide a structural basis for a dual role of survivin in inhibition of apoptosis and regulation of cell division.
Li et al. (1998) showed that survivin is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of the antiapoptosis function of survivin and increased activity of caspase-3 (CASP3;600636), a mechanism involved in cell death, during mitosis. These results indicated that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome an apoptotic checkpoint and favor aberrant progression of transformed cells through mitosis.
Baculoviral IAP repeat proteins (BIRPs) may affect cell death, cell division, and tumorigenesis.Speliotes et al. (2000) reported that Bir1, a C. elegans BIRP that is homologous to the human API4 protein (survivin), was localized to chromosomes and to the spindle midzone. Embryos and fertilized oocytes lacking Bir1 had defects in chromosome behavior, spindle midzone formation, and cytokinesis. The authors observed indistinguishable defects in fertilized oocytes and embryos lacking the Aurora (see604970)-like kinase Air2. Air2 was not present on chromosomes in the absence of Bir1. Histone H3 phosphorylation and Hcp1 staining, which marks kinetochores, were reduced in the absence of either Bir1 or Air2.Speliotes et al. (2000) proposed that Bir1 localizes Air2 to chromosomes and perhaps to the spindle midzone, where Air2 phosphorylates proteins that affect chromosome behavior and spindle midzone organization. Survivin, which is upregulated in tumors, could partially substitute for Bir1 in C. elegans. Deregulation of Bir1 promotes changes in ploidy, suggesting that similar deregulation of mammalian BIRPs may contribute to tumorigenesis.
Adida et al. (2000) studied expression and prognostic significance of survivin in 222 patients with diffuse large B-cell lymphomas. The results suggested that survivin expression is an unfavorable prognostic factor in this disorder.
Grossman et al. (2001) investigated the role of apoptosis in tumor formation and growth by targeting the apoptosis inhibitor survivin in vivo. Expression of a phosphorylation-defective survivin mutant (thr34 to ala) triggered apoptosis in several human melanoma cell lines and enhanced cell death induced by the chemotherapeutic drug cisplatin in vitro. Conditional expression of the mutant survivin in a melanoma cell line prevented tumor formation upon subcutaneous injection into beige Scid mice. When induced in established melanoma tumors, the mutant survivin inhibited tumor growth by 60 to 70% and caused increased apoptosis and reduced proliferation of melanoma cells in vivo. Manipulation of the antiapoptotic pathway maintained by survivin may be beneficial for cancer therapy.
Smith et al. (2001) checked for the presence of survivin in urine samples from 5 groups (patients with genitourinary cancer, new-onset or recurrent bladder cancer, treated bladder cancer, nonneoplastic urinary tract disease, and controls) using a simple, antibody-based test, confirmed by Western blot and RT-PCR. The authors concluded that their urine survivin test is a highly sensitive and specific diagnostic test to identify patients with new or recurrent bladder cancer.
Increased expression of survivin was shown to be a negative predictor of survival in patients with soft tissue sarcoma. In a study of 89 adults with soft tissue sarcomas,Wurl et al. (2002) determined that coexpression of survivin and TERT (187270) transcripts identifies patients at high risk of tumor-related death.
Blanc-Brude et al. (2002) showed that balloon-mediated arterial injury in rabbits results in expression of survivin in vascular cells. Expression of survivin in cultured smooth muscle cells was stimulated by serum or platelet-derived growth factor (see173430) and suppressed apoptosis and prevented caspase activation. These and other data identified survivin as a critical regulator of smooth muscle cell apoptosis after acute vascular injury. Disrupting the survivin pathway may provide a novel therapy to limit pathologic vessel wall remodeling.
Mirza et al. (2002) showed that wildtype p53 (191170) represses survivin expression at both the mRNA and protein levels. Transient transfection analyses revealed that the expression of wildtype p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The overexpression of exogenous survivin protein rescued cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least in part, the p53-dependent apoptotic pathway. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.Esteve et al. (2005) found that DNMT1 (126375) bound p53 and that cooperation between DNMT1 and p53 is essential for the repression of endogenous survivin.
Ueda et al. (2002) investigated survivin gene and protein expression in a tumor-like benign disease, endometriosis, and correlated them with apoptosis and invasive phenotype of endometriotic tissues. Gene expression levels of survivin, MMP2 (120360), MMP9 (120361), and MMP14 (600754) in 63 pigmented or nonpigmented endometriotic tissues surgically obtained from 35 women with endometriosis were compared with those in normal eutopic endometrium obtained from 12 women without endometriosis. Survivin, MMP2, MMP9, and MMP14 mRNA expression levels in clinically aggressive pigmented lesions were significantly higher than those in normal eutopic endometrium, and survivin gene expression in pigmented lesions was also higher than that in nonpigmented lesions (P less than 0.05). There was a close correlation between survivin and MMP2, MMP9, and MMP14 gene expression levels in 63 endometriotic tissues examined (P less than 0.01). The authors concluded that upregulation of survivin and MMPs may cooperatively contribute to survival and invasion of endometriosis.
In patients with multiple sclerosis (MS;126200), treatment with interferon-beta reduces clinical exacerbations and disease burden via multiple immunomodulatory actions, including augmentation of apoptosis. In 10 of 18 patients with MS who responded to interferon-beta therapy,Sharief and Semra (2002) found a significant decline in cellular survivin expression after 6 and 12 months. Specifically, T-cell susceptibility to etoposide-induced apoptosis was increased in these patients, findings that were confirmed by in vitro experiments. These results suggested at least 1 mechanism by which interferon-beta treatment is effective in some patients with MS.
Marusawa et al. (2003) found that survivin interacts with hepatitis B virus X protein (HBX)-interacting protein (HBXIP;608521). Survivin-HBXIP complexes, but neither protein alone, bound procaspase-9 (602234) and prevented its recruitment to APAF1 (602233), thereby selectively suppressing apoptosis initiated via the mitochondria/cytochrome c (123970) pathway. Viral HBX protein also interacted with the survivin-HBXIP complex and suppressed caspase activation in a survivin-dependent manner.Marusawa et al. (2003) concluded that HBXIP functions as a cofactor for survivin and serves as a link between the cellular apoptosis machinery and a viral pathogen involved in hepatocellular carcinogenesis.
Using immunohistochemistry,McMurtry et al. (2005) demonstrated that survivin was expressed in the pulmonary arteries of 6 patients with pulmonary arterial hypertension (PAH) and rats with monocrotaline-induced PAH but not in the pulmonary arteries of 3 patients and rats without PAH. Gene therapy in rats with PAH using a survivin mutant with dominant-negative properties lowered pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary artery medial hypertrophy, and prolonged survival by 25%. Both in vitro and in vivo, inhibition of survivin induced pulmonary artery smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor (300169) into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of wildtype survivin.
By quantitative immunostaining,Asanuma et al. (2004) found a correlation between expression of survivin and FASL (TNFSF6;134638) in colon cancer tissues. Transfection of survivin into a colon cancer cell line upregulated FASL expression and increased cytotoxicity against a FAS (TNFRSF6;134637)-sensitive T-cell line. Transfected cells showed increased DNA binding of the transcription factor SP1 (189906) to the FASL promoter and upregulation of SP1 phosphorylation at ser and thr residues; the total amount of SP1 was not changed. Inhibition of survivin expression in a colon cancer cell line by small interfering RNA downregulated FASL expression.Asanuma et al. (2004) concluded that survivin enables cancer cells not only to suppress immune cell attack by inhibiting FAS-mediated apoptosis, but also to attack immune cells by induction of FASL.
Proper chromosome segregation requires the attachment of sister kinetochores to microtubules from opposite spindle poles to form bioriented chromosomes on the metaphase spindle. The chromosome passenger complex containing survivin and the kinase aurora B (604970) regulates this process from the centromeres.Vong et al. (2005) reported that a deubiquitinating enzyme, FAM, also known as USP9X (300072), regulates chromosome alignment and segregation by controlling both the dynamic association of survivin with centromeres and the proper targeting of survivin and aurora B to centromeres. Survivin is ubiquitinated in mitosis through both lys48 and lys63 ubiquitin linkages. Lys63 deubiquitination mediated by FAM is required for the dissociation of survivin from centromeres, whereas lys63 ubiquitination mediated by the ubiquitin-binding protein UFD1 (601754) is required for the association of survivin with centromeres. Thus, ubiquitination regulates dynamic protein-protein interactions and chromosome segregation independently of protein degradation.
Survivin is proposed to play a central role in the progression and resistance to therapy of diverse tumor types. High levels of this molecule in tumor cells also correlate with loss of the TP53 tumor suppressor gene (191170), suggesting a molecular connection between TP53 loss and transcriptional induction of survivin. Patients who had TP53 germline mutations, such as those with Li-Fraumeni syndrome, are particularly susceptible to sarcomas, including rhabdomyosarcomas. In a study of 63 primary rhabdomyosarcoma tumors,Caldas et al. (2006) found that more than 80% expressed survivin. Treatment of rhabdomyosarcoma xenografts by survivin-directed RNA interference showed greater than 70% reduction in growth when compared with control injected tumors.
Although erythroid cells and megakaryocytes arise from a common progenitor, their terminal maturation is different; erythroid cells undergo cell cycle exit and enucleation, whereas megakaryocytes continue to progress through the cell cycle but skip late stages of mitosis to become polyploid cells.Gurbuxani et al. (2005) found that survivin was differentially expressed during erythroid versus megakaryocyte development in human and mouse cell lines. Erythroid cells expressed survivin throughout their maturation, whereas megakaryocytes expressed about 4-fold lower survivin mRNA and no detectable protein. Overexpression of survivin in mouse bone marrow cells antagonized megakaryocyte growth, maturation, and polyploidization, but it had no effect on erythroid development. In contrast, knockdown of survivin expression interfered with formation of erythroid cells but not megakaryocytes. Survivin-deficient hematopoietic progenitors failed to give rise to either erythroid or megakaryocytic colonies.Gurbuxani et al. (2005) concluded that survivin is essential for megakaryocyte and erythroid progenitors and that its downregulation is required for terminal differentiation of megakaryocytes.
Dohi et al. (2007) stated that the antiapoptotic function of survivin appears to rely on interactions with other molecules, including XIAP (300079), and that mitochondrial and cytosolic survivin differ with respect to cell death inhibition. Using rat and human cells,Dohi et al. (2007) showed that protein kinase A (see176911) phosphorylated survivin in the cytosol, but not in mitochondria. This phosphorylation event disrupted the binding interface between survivin and XIAP. Conversely, mitochondrial survivin or a nonphosphorylatable survivin mutant bound XIAP avidly, enhanced XIAP stability, synergistically inhibited apoptosis, and accelerated tumor growth in immunocompromised mice.Dohi et al. (2007) concluded that differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP.
Wang et al. (2008) found lower expression of SIRT1 (604479) in mouse and human BRCA1 (113705)-associated breast cancers compared with controls. Reduced Sirt1 expression in Brca1-mutant mice was associated with increased expression of survivin, and this expression pattern as reversed by induced expression of Brca1.Wang et al. (2008) showed that BRCA1 bound to the SIRT1 promoter and increased SIRT1 expression, which in turn inhibited survivin expression. Furthermore, inhibition of Brca1-mutant tumor growth by the anticancer agent resveratrol was associated with upregulation of Sirt1 activity, followed by reduction in survivin and apoptosis of the tumor cells.
Kelly et al. (2010) independently demonstrated that histone H3 phosphorylated at threonine-3 (H3T3ph) is directly recognized by an evolutionarily conserved binding pocket in the BIR domain of survivin, which is a member of the chromosomal passenger complex (CPC). This binding mediates recruitment of the CPC to chromosomes and the resulting activation of its kinase subunit Aurora B (604970). Consistently, modulation of the kinase activity of haspin (609240), which phosphorylates H3T3, leads to defects in the Aurora B-dependent processes of spindle assembly and inhibition of nuclear reformation.Kelly et al. (2010) concluded that their findings established a direct cellular role for mitotic H3T3 phosphorylation, which is read and translated by the CPC to ensure accurate cell division.
Yamagishi et al. (2010) showed that phosphorylation of H3T3 mediated by haspin cooperates with bub1 (602452)-mediated histone 2A-serine-121 (H2A-S121) phosphorylation in targeting the CPC to the inner centromere in fission yeast and human cells. Phosphorylated H3T3 promotes nucleosome binding of survivin, whereas phosphorylated H2A-S121 facilitates the binding of shugoshin (609168), the centromeric CPC adaptor. Haspin colocalizes with cohesin by associating with Pds5 (see613200), whereas bub1 localizes at kinetochores. Thus,Yamagishi et al. (2010) concluded that the inner centromere is defined by intersection of 2 histone kinases.
Regulation of Survivin Expression by EPR1
Ambrosini et al. (1998) showed that overexpression of EPR1 caused HeLa cells to undergo apoptosis concomitant with downregulation of survivin expression. Overexpression of survivin was without effect.
Using RT-PCR,Shinozawa et al. (2000) detected EPR1 expression in all normal peripheral blood, bone marrow, and lymph node samples examined. In contrast, few normal tissues expressed survivin. The expression profiles of EPR1 and survivin were reversed in leukemia cell lines and hematologic malignancies, with a high proportion of disease tissues expressing survivin and few expressing EPR1.
Yamamoto et al. (2002) found that induction of EPR1 in HT29 human colon adenocarcinoma cells downregulated survivin expression, decreased cell proliferation, and increased apoptosis and sensitivity to anticancer agents. Subcutaneous tumors developed in nude mice from EPR1-expressing HT29 cells were smaller than tumors grown from parental HT29 cells, and this antitumor function of EPR1 was enhanced when combined with anticancer agents.Yamamoto et al. (2002) concluded that EPR1 functions as a natural antisense transcript that regulates survivin expression.
Reviews
For a review of survivin, seeAltieri and Marchisio (1999).
Using flow cytometric analysis,Tao et al. (2005) found that NKT cells from patients with active systemic lupus erythematosus (SLE;152700) were more susceptible to apoptosis induced by anti-CD95 (TNFRSF6;134637) than NKT cells from patients with inactive SLE or normal controls. Further analysis suggested that deficient expression of CD226 (605397) and survivin in NKT cells from patients with active SLE may explain the sensitivity of these cells to apoptosis. However, in 2012,Tao et al. (2005) retracted their paper.
Adida, C., Crotty, P. L., McGrath, J., Berrebi, D., Diebold, J., Altieri, D. C.Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am. J. Path. 152: 43-49, 1998. [PubMed:9422522,related citations]
Adida, C., Haioun, C., Gaulard, P., Lepage, E., Morel, P., Briere, J., Dombret, H., Reyes, F., Diebold, J., Gisselbrecht, C., Salles, G., Altieri, D. C., Molina, T. J.Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood 96: 1921-1925, 2000. [PubMed:10961895,related citations]
Altieri, D. C., Marchisio, P. C.Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab. Invest. 79: 1327-1333, 1999. Note: Erratum: Lab. Invest. 79: 1543 only, 1999. [PubMed:10576203,related citations]
Ambrosini, G., Adida, C., Altieri, D. C.A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nature Med. 3: 917-921, 1997. [PubMed:9256286,related citations] [Full Text]
Ambrosini, G., Adida, C., Sirugo, G., Altieri, D. C.Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J. Biol. Chem. 273: 11177-11182, 1998. [PubMed:9556606,related citations] [Full Text]
Asanuma, K., Tsuji, N., Endoh, T., Yagihashi, A., Watanabe, N.Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells. J. Immun. 172: 3922-3929, 2004. [PubMed:15004200,related citations] [Full Text]
Blanc-Brude, O. P., Yu, J., Simosa, H., Conte, M. S., Sessa, W. C., Altieri, D. C.Inhibitor of apoptosis protein survivin regulates vascular injury. Nature Med. 8: 987-994, 2002. [PubMed:12172543,related citations] [Full Text]
Caldas, H., Holloway, M. P., Hall, B. M., Qualman, S. J., Altura, R. A.Survivin-directed RNA interference cocktail is a potent suppressor of tumour growth in vivo. J. Med. Genet. 43: 119-128, 2006. Note: Erratum: J. Med. Genet. 43: 418 only, 2006. [PubMed:15908567,images,related citations] [Full Text]
Chantalat, L., Skoufias, D. A., Kleman, J.-P., Jung, B., Dideberg, O., Margolis, R. L.Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. Molec. Cell 6: 183-189, 2000. [PubMed:10949039,related citations]
Dohi, T., Xia, F., Altieri, D. C.Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection. Molec. Cell 27: 17-28, 2007. [PubMed:17612487,images,related citations] [Full Text]
Esteve, P.-O., Chin, H. G., Pradhan, S.Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc. Nat. Acad. Sci. 102: 1000-1005, 2005. [PubMed:15657147,images,related citations] [Full Text]
Grossman, D., Kim, P. J., Schechner, J. S., Altieri, D. C.Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc. Nat. Acad. Sci. 98: 635-640, 2001. [PubMed:11149963,images,related citations] [Full Text]
Gurbuxani, S., Xu, Y., Keerthivasan, G., Wickrema, A., Crispino, J. D.Differential requirements for survivin in hematopoietic cell development. Proc. Nat. Acad. Sci. 102: 11480-11485, 2005. [PubMed:16055565,images,related citations] [Full Text]
Kelly, A. E., Ghenoiu, C., Xue, J. Z., Zierhut, C., Kimura, H., Funabiki, H.Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B. Science 330: 235-239, 2010. [PubMed:20705815,images,related citations] [Full Text]
Li, F., Ambrosini, G., Chu, E. Y., Plescia, J., Tognin, S., Marchisio, P. C., Altieri, D. C.Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396: 580-584, 1998. [PubMed:9859993,related citations] [Full Text]
Marusawa, H., Matsuzawa, S., Welsh, K., Zou, H., Armstrong, R., Tamm, I., Reed, J. C.HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J. 22: 2729-2740, 2003. [PubMed:12773388,images,related citations] [Full Text]
McMurtry, M. S., Archer, S. L., Altieri, D. C., Bonnet, S., Haromy, A., Harry, G., Bonnet, S., Puttagunta, L., Michelakis, E. D.Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J. Clin. Invest. 115: 1479-1491, 2005. [PubMed:15931388,images,related citations] [Full Text]
Mirza, A., McGuirk, M., Hockenberry, T. N., Wu, Q., Ashar, H., Black, S., Wen, S. F., Wang, L., Kirschmeier, P., Bishop, W. R., Nielsen, L. L., Pickett, C. B., Liu, S.Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21: 2613-2622, 2002. [PubMed:11965534,related citations] [Full Text]
Muchmore, S. W., Chen, J., Jakob, C., Zakula, D., Matayoshi, E. D., Wu, W., Zhang, H., Li, F., Ng, S.-C., Altieri, D. C.Crystal structure and mutagenic analysis of the inhibitor-of-apoptosis protein survivin. Molec. Cell 6: 173-182, 2000. [PubMed:10949038,related citations]
Sharief, M. K., Semra, Y. K.Down-regulation of survivin expression in T lymphocytes after interferon beta-1a treatment in patients with multiple sclerosis. Arch. Neurol. 59: 1115-1121, 2002. [PubMed:12117359,related citations] [Full Text]
Shinozawa, I., Inokuchi, K., Wakabayashi, I., Dan, K.Disturbed expression of the anti-apoptosis gene, survivin, and EPR-1 in hematological malignancies. Leukemia Res. 24: 965-970, 2000. [PubMed:11086180,related citations] [Full Text]
Smith, S. D., Wheeler, M. A., Plescia, J., Colberg, J. W., Weiss, R. M., Altieri, D. C.Urine detection of survivin and diagnosis of bladder cancer. JAMA 285: 324-328, 2001. [PubMed:11176843,related citations] [Full Text]
Speliotes, E. K., Uren, A., Vaux, D., Horvitz, H. R.The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Molec. Cell 6: 211-223, 2000. [PubMed:10983970,related citations] [Full Text]
Tao, D., Shangwu, L., Qun, W., Yan, L., Wei, J., Junyan, L., Feili, G., Boquan, J., Jinquan, T.CD226 expression deficiency causes high sensitivity to apoptosis in NK T cells from patients with systemic lupus erythematosus. J. Immun. 174: 1281-1290, 2005. Note: Retraction: J. Immun. 188: 5800 only, 2012. [PubMed:15661884,related citations] [Full Text]
Ueda, M., Yamashita, Y., Takehara, M., Terai, Y., Kumagai, K., Ueki, K., Kanda, K., Yamaguchi, H., Akise, D., Hung, Y.-C., Ueki, M.Survivin gene expression in endometriosis. J. Clin. Endocr. Metab. 87: 3452-3459, 2002. [PubMed:12107265,related citations] [Full Text]
Vong, Q. P., Cao, K., Li, H. Y., Iglesias, P. A., Zheng, Y.Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 310: 1499-1504, 2005. [PubMed:16322459,related citations] [Full Text]
Wang, R.-H., Zheng, Y., Kim, H.-S., Xu, X., Cao, L., Luhasen, T., Lee, M.-H., Xiao, C., Vassilopoulos, A., Chen, W., Gardner, K., Man, Y.-G., Hung, M.-C., Finkel, T., Deng, C.-X.Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Molec. Cell 32: 11-20, 2008. [PubMed:18851829,images,related citations] [Full Text]
Wurl, P., Kappler, M., Meye, A., Bartel, F., Kohler, T., Lautenschlager, C., Bache, M., Schmidt, H., Taubert, H.Co-expression of survivin and TERT and risk of tumour-related death in patients with soft-tissue sarcoma. Lancet 359: 943-945, 2002. [PubMed:11918915,related citations] [Full Text]
Yamagishi, Y., Honda, T., Tanno, Y., Watanabe, Y.Two histone marks establish the inner centromere and chromosome bi-orientation. Science 330: 239-233, 2010. [PubMed:20929775,related citations] [Full Text]
Yamamoto, T., Manome, Y., Nakamura, M., Tanigawa, N.Downregulation of survivin expression by induction of the effector cell protease receptor-1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents in human colon cancer. Europ. J. Cancer 38: 2316-2324, 2002. [PubMed:12441269,related citations] [Full Text]
Zaman, G. J. R., Conway, E. M.The elusive factor Xa receptor: failure to detect transcripts that correspond to the published sequence of EPR-1. Blood 96: 145-148, 2000. [PubMed:10891443,related citations]
Alternative titles; symbols
HGNC Approved Gene Symbol: BIRC5
Cytogenetic location: 17q25.3 Genomic coordinates(GRCh38) : 17:78,214,253-78,225,635(from NCBI)
BIRC5 is an inhibitor of apoptosis (IAP), or programmed cell death, that is selectively overexpressed in common human cancers (Ambrosini et al., 1997).
Progression of the cell cycle and control of apoptosis are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. By hybridization screening of a human genomic library with an EPR1 (603411) probe, Ambrosini et al. (1997) isolated a cDNA encoding an inhibitor of apoptosis (IAP) protein, which they termed survivin. Survivin, also termed API4, encodes a deduced 142-amino acid protein. Sequence analysis revealed that survivin lacks a signal peptide and a hydrophobic domain for membrane insertion. Unlike other IAPs, survivin contains only 1 copy, rather than 2 or 3, of the baculovirus IAP repeat cys/his-based zinc finger, which is essential for apoptosis inhibition (see, e.g., 601712), and a C-terminal RING finger (e.g., RNF5 602677). Survivin has 6 potential phosphorylation sites. Western blot analysis showed a 16.5-kD protein in transformed but not untransformed cell lines. By Northern blot analysis, Ambrosini et al. (1997) observed expression of a 1.9-kb transcript predominantly in fetal kidney and liver and to a lesser extent in fetal lung and brain. Expression was not observed in adult tissue except for thymus and placenta. Immunohistochemical and in situ hybridization analyses of tumor tissues revealed abundant expression in adenocarcinomas of lung, pancreas, breast, and prostate as well as in squamous lung cell carcinoma. Adjacent nonneoplastic tissue lacked survivin expression. Survivin is also expressed in high-grade but not low-grade non-Hodgkin lymphoma.
Adida et al. (1998) found high expression of survivin in multiple tissues in fetuses at least through week 21. Likewise, in the mouse, expression is detectable at embryonic day 11.5 but not after day embryonic day 14.
Using strand-specific probes for Northern blot analysis, Ambrosini et al. (1998) detected a prominent 1.3-kb transcript for EPR1, which is antisense to survivin on chromosome 17, in most adult and terminally differentiated human tissues examined. The 1.3-kb EPR1 transcript was also detected in all fetal tissues examined. In contrast, a major 1.9-kb transcript for survivin was detected only in transformed cell lines.
Independently, Zaman and Conway (2000) assayed the expression of EPR1 and survivin in human tissues with strand-specific probes. A survivin transcript of about 1.9 kb was detected in several tissues. Major EPR1 transcripts of 2.0, 1.6, and 1.0 kb were detected in various tissues depending on the probe used, with the 1.6-kb transcript present in all tissues.
Ambrosini et al. (1997) determined that the BIRC5 gene contains 4 exons.
Ambrosini et al. (1998) mapped the BIRC5 gene to chromosome 17q25 by pulsed field gel electrophoresis and single- and 2-color FISH. It is oriented in the opposite direction from EPR1 on the complementary strand.
By x-ray crystallography, Chantalat et al. (2000) determined the structure of the full-length human survivin to 2.7 angstroms. Strikingly, the structure forms a very unusual bow tie-shaped dimer. It does not dimerize through a C-terminal coiled coil, contrary to sequence analysis prediction. The C-terminal helices contain hydrophobic clusters with the potential for protein-protein interactions. Chantalat et al. (2000) concluded that the unusual shape and dimensions of survivin suggest that it serves an adaptor function through its alpha-helical extensions.
Muchmore et al. (2000) reported the crystal structure of survivin. In addition to a conserved N-terminal zinc finger baculovirus IAP repeat, survivin forms a dimer through a symmetric interaction with an intermolecularly bound zinc atom located along the molecular dyad axis. The interaction of the dimer-related C-terminal alpha helices forms an extended surface of approximately 70 angstroms in length. Mutagenesis analysis revealed that survivin dimerization and an extended negatively charged surface surrounding asp71 are required to counteract apoptosis and preserve ploidy. Muchmore et al. (2000) suggested that these findings may provide a structural basis for a dual role of survivin in inhibition of apoptosis and regulation of cell division.
Li et al. (1998) showed that survivin is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of the antiapoptosis function of survivin and increased activity of caspase-3 (CASP3; 600636), a mechanism involved in cell death, during mitosis. These results indicated that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome an apoptotic checkpoint and favor aberrant progression of transformed cells through mitosis.
Baculoviral IAP repeat proteins (BIRPs) may affect cell death, cell division, and tumorigenesis. Speliotes et al. (2000) reported that Bir1, a C. elegans BIRP that is homologous to the human API4 protein (survivin), was localized to chromosomes and to the spindle midzone. Embryos and fertilized oocytes lacking Bir1 had defects in chromosome behavior, spindle midzone formation, and cytokinesis. The authors observed indistinguishable defects in fertilized oocytes and embryos lacking the Aurora (see 604970)-like kinase Air2. Air2 was not present on chromosomes in the absence of Bir1. Histone H3 phosphorylation and Hcp1 staining, which marks kinetochores, were reduced in the absence of either Bir1 or Air2. Speliotes et al. (2000) proposed that Bir1 localizes Air2 to chromosomes and perhaps to the spindle midzone, where Air2 phosphorylates proteins that affect chromosome behavior and spindle midzone organization. Survivin, which is upregulated in tumors, could partially substitute for Bir1 in C. elegans. Deregulation of Bir1 promotes changes in ploidy, suggesting that similar deregulation of mammalian BIRPs may contribute to tumorigenesis.
Adida et al. (2000) studied expression and prognostic significance of survivin in 222 patients with diffuse large B-cell lymphomas. The results suggested that survivin expression is an unfavorable prognostic factor in this disorder.
Grossman et al. (2001) investigated the role of apoptosis in tumor formation and growth by targeting the apoptosis inhibitor survivin in vivo. Expression of a phosphorylation-defective survivin mutant (thr34 to ala) triggered apoptosis in several human melanoma cell lines and enhanced cell death induced by the chemotherapeutic drug cisplatin in vitro. Conditional expression of the mutant survivin in a melanoma cell line prevented tumor formation upon subcutaneous injection into beige Scid mice. When induced in established melanoma tumors, the mutant survivin inhibited tumor growth by 60 to 70% and caused increased apoptosis and reduced proliferation of melanoma cells in vivo. Manipulation of the antiapoptotic pathway maintained by survivin may be beneficial for cancer therapy.
Smith et al. (2001) checked for the presence of survivin in urine samples from 5 groups (patients with genitourinary cancer, new-onset or recurrent bladder cancer, treated bladder cancer, nonneoplastic urinary tract disease, and controls) using a simple, antibody-based test, confirmed by Western blot and RT-PCR. The authors concluded that their urine survivin test is a highly sensitive and specific diagnostic test to identify patients with new or recurrent bladder cancer.
Increased expression of survivin was shown to be a negative predictor of survival in patients with soft tissue sarcoma. In a study of 89 adults with soft tissue sarcomas, Wurl et al. (2002) determined that coexpression of survivin and TERT (187270) transcripts identifies patients at high risk of tumor-related death.
Blanc-Brude et al. (2002) showed that balloon-mediated arterial injury in rabbits results in expression of survivin in vascular cells. Expression of survivin in cultured smooth muscle cells was stimulated by serum or platelet-derived growth factor (see 173430) and suppressed apoptosis and prevented caspase activation. These and other data identified survivin as a critical regulator of smooth muscle cell apoptosis after acute vascular injury. Disrupting the survivin pathway may provide a novel therapy to limit pathologic vessel wall remodeling.
Mirza et al. (2002) showed that wildtype p53 (191170) represses survivin expression at both the mRNA and protein levels. Transient transfection analyses revealed that the expression of wildtype p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The overexpression of exogenous survivin protein rescued cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least in part, the p53-dependent apoptotic pathway. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53. Esteve et al. (2005) found that DNMT1 (126375) bound p53 and that cooperation between DNMT1 and p53 is essential for the repression of endogenous survivin.
Ueda et al. (2002) investigated survivin gene and protein expression in a tumor-like benign disease, endometriosis, and correlated them with apoptosis and invasive phenotype of endometriotic tissues. Gene expression levels of survivin, MMP2 (120360), MMP9 (120361), and MMP14 (600754) in 63 pigmented or nonpigmented endometriotic tissues surgically obtained from 35 women with endometriosis were compared with those in normal eutopic endometrium obtained from 12 women without endometriosis. Survivin, MMP2, MMP9, and MMP14 mRNA expression levels in clinically aggressive pigmented lesions were significantly higher than those in normal eutopic endometrium, and survivin gene expression in pigmented lesions was also higher than that in nonpigmented lesions (P less than 0.05). There was a close correlation between survivin and MMP2, MMP9, and MMP14 gene expression levels in 63 endometriotic tissues examined (P less than 0.01). The authors concluded that upregulation of survivin and MMPs may cooperatively contribute to survival and invasion of endometriosis.
In patients with multiple sclerosis (MS; 126200), treatment with interferon-beta reduces clinical exacerbations and disease burden via multiple immunomodulatory actions, including augmentation of apoptosis. In 10 of 18 patients with MS who responded to interferon-beta therapy, Sharief and Semra (2002) found a significant decline in cellular survivin expression after 6 and 12 months. Specifically, T-cell susceptibility to etoposide-induced apoptosis was increased in these patients, findings that were confirmed by in vitro experiments. These results suggested at least 1 mechanism by which interferon-beta treatment is effective in some patients with MS.
Marusawa et al. (2003) found that survivin interacts with hepatitis B virus X protein (HBX)-interacting protein (HBXIP; 608521). Survivin-HBXIP complexes, but neither protein alone, bound procaspase-9 (602234) and prevented its recruitment to APAF1 (602233), thereby selectively suppressing apoptosis initiated via the mitochondria/cytochrome c (123970) pathway. Viral HBX protein also interacted with the survivin-HBXIP complex and suppressed caspase activation in a survivin-dependent manner. Marusawa et al. (2003) concluded that HBXIP functions as a cofactor for survivin and serves as a link between the cellular apoptosis machinery and a viral pathogen involved in hepatocellular carcinogenesis.
Using immunohistochemistry, McMurtry et al. (2005) demonstrated that survivin was expressed in the pulmonary arteries of 6 patients with pulmonary arterial hypertension (PAH) and rats with monocrotaline-induced PAH but not in the pulmonary arteries of 3 patients and rats without PAH. Gene therapy in rats with PAH using a survivin mutant with dominant-negative properties lowered pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary artery medial hypertrophy, and prolonged survival by 25%. Both in vitro and in vivo, inhibition of survivin induced pulmonary artery smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor (300169) into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of wildtype survivin.
By quantitative immunostaining, Asanuma et al. (2004) found a correlation between expression of survivin and FASL (TNFSF6; 134638) in colon cancer tissues. Transfection of survivin into a colon cancer cell line upregulated FASL expression and increased cytotoxicity against a FAS (TNFRSF6; 134637)-sensitive T-cell line. Transfected cells showed increased DNA binding of the transcription factor SP1 (189906) to the FASL promoter and upregulation of SP1 phosphorylation at ser and thr residues; the total amount of SP1 was not changed. Inhibition of survivin expression in a colon cancer cell line by small interfering RNA downregulated FASL expression. Asanuma et al. (2004) concluded that survivin enables cancer cells not only to suppress immune cell attack by inhibiting FAS-mediated apoptosis, but also to attack immune cells by induction of FASL.
Proper chromosome segregation requires the attachment of sister kinetochores to microtubules from opposite spindle poles to form bioriented chromosomes on the metaphase spindle. The chromosome passenger complex containing survivin and the kinase aurora B (604970) regulates this process from the centromeres. Vong et al. (2005) reported that a deubiquitinating enzyme, FAM, also known as USP9X (300072), regulates chromosome alignment and segregation by controlling both the dynamic association of survivin with centromeres and the proper targeting of survivin and aurora B to centromeres. Survivin is ubiquitinated in mitosis through both lys48 and lys63 ubiquitin linkages. Lys63 deubiquitination mediated by FAM is required for the dissociation of survivin from centromeres, whereas lys63 ubiquitination mediated by the ubiquitin-binding protein UFD1 (601754) is required for the association of survivin with centromeres. Thus, ubiquitination regulates dynamic protein-protein interactions and chromosome segregation independently of protein degradation.
Survivin is proposed to play a central role in the progression and resistance to therapy of diverse tumor types. High levels of this molecule in tumor cells also correlate with loss of the TP53 tumor suppressor gene (191170), suggesting a molecular connection between TP53 loss and transcriptional induction of survivin. Patients who had TP53 germline mutations, such as those with Li-Fraumeni syndrome, are particularly susceptible to sarcomas, including rhabdomyosarcomas. In a study of 63 primary rhabdomyosarcoma tumors, Caldas et al. (2006) found that more than 80% expressed survivin. Treatment of rhabdomyosarcoma xenografts by survivin-directed RNA interference showed greater than 70% reduction in growth when compared with control injected tumors.
Although erythroid cells and megakaryocytes arise from a common progenitor, their terminal maturation is different; erythroid cells undergo cell cycle exit and enucleation, whereas megakaryocytes continue to progress through the cell cycle but skip late stages of mitosis to become polyploid cells. Gurbuxani et al. (2005) found that survivin was differentially expressed during erythroid versus megakaryocyte development in human and mouse cell lines. Erythroid cells expressed survivin throughout their maturation, whereas megakaryocytes expressed about 4-fold lower survivin mRNA and no detectable protein. Overexpression of survivin in mouse bone marrow cells antagonized megakaryocyte growth, maturation, and polyploidization, but it had no effect on erythroid development. In contrast, knockdown of survivin expression interfered with formation of erythroid cells but not megakaryocytes. Survivin-deficient hematopoietic progenitors failed to give rise to either erythroid or megakaryocytic colonies. Gurbuxani et al. (2005) concluded that survivin is essential for megakaryocyte and erythroid progenitors and that its downregulation is required for terminal differentiation of megakaryocytes.
Dohi et al. (2007) stated that the antiapoptotic function of survivin appears to rely on interactions with other molecules, including XIAP (300079), and that mitochondrial and cytosolic survivin differ with respect to cell death inhibition. Using rat and human cells, Dohi et al. (2007) showed that protein kinase A (see 176911) phosphorylated survivin in the cytosol, but not in mitochondria. This phosphorylation event disrupted the binding interface between survivin and XIAP. Conversely, mitochondrial survivin or a nonphosphorylatable survivin mutant bound XIAP avidly, enhanced XIAP stability, synergistically inhibited apoptosis, and accelerated tumor growth in immunocompromised mice. Dohi et al. (2007) concluded that differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP.
Wang et al. (2008) found lower expression of SIRT1 (604479) in mouse and human BRCA1 (113705)-associated breast cancers compared with controls. Reduced Sirt1 expression in Brca1-mutant mice was associated with increased expression of survivin, and this expression pattern as reversed by induced expression of Brca1. Wang et al. (2008) showed that BRCA1 bound to the SIRT1 promoter and increased SIRT1 expression, which in turn inhibited survivin expression. Furthermore, inhibition of Brca1-mutant tumor growth by the anticancer agent resveratrol was associated with upregulation of Sirt1 activity, followed by reduction in survivin and apoptosis of the tumor cells.
Kelly et al. (2010) independently demonstrated that histone H3 phosphorylated at threonine-3 (H3T3ph) is directly recognized by an evolutionarily conserved binding pocket in the BIR domain of survivin, which is a member of the chromosomal passenger complex (CPC). This binding mediates recruitment of the CPC to chromosomes and the resulting activation of its kinase subunit Aurora B (604970). Consistently, modulation of the kinase activity of haspin (609240), which phosphorylates H3T3, leads to defects in the Aurora B-dependent processes of spindle assembly and inhibition of nuclear reformation. Kelly et al. (2010) concluded that their findings established a direct cellular role for mitotic H3T3 phosphorylation, which is read and translated by the CPC to ensure accurate cell division.
Yamagishi et al. (2010) showed that phosphorylation of H3T3 mediated by haspin cooperates with bub1 (602452)-mediated histone 2A-serine-121 (H2A-S121) phosphorylation in targeting the CPC to the inner centromere in fission yeast and human cells. Phosphorylated H3T3 promotes nucleosome binding of survivin, whereas phosphorylated H2A-S121 facilitates the binding of shugoshin (609168), the centromeric CPC adaptor. Haspin colocalizes with cohesin by associating with Pds5 (see 613200), whereas bub1 localizes at kinetochores. Thus, Yamagishi et al. (2010) concluded that the inner centromere is defined by intersection of 2 histone kinases.
Regulation of Survivin Expression by EPR1
Ambrosini et al. (1998) showed that overexpression of EPR1 caused HeLa cells to undergo apoptosis concomitant with downregulation of survivin expression. Overexpression of survivin was without effect.
Using RT-PCR, Shinozawa et al. (2000) detected EPR1 expression in all normal peripheral blood, bone marrow, and lymph node samples examined. In contrast, few normal tissues expressed survivin. The expression profiles of EPR1 and survivin were reversed in leukemia cell lines and hematologic malignancies, with a high proportion of disease tissues expressing survivin and few expressing EPR1.
Yamamoto et al. (2002) found that induction of EPR1 in HT29 human colon adenocarcinoma cells downregulated survivin expression, decreased cell proliferation, and increased apoptosis and sensitivity to anticancer agents. Subcutaneous tumors developed in nude mice from EPR1-expressing HT29 cells were smaller than tumors grown from parental HT29 cells, and this antitumor function of EPR1 was enhanced when combined with anticancer agents. Yamamoto et al. (2002) concluded that EPR1 functions as a natural antisense transcript that regulates survivin expression.
Reviews
For a review of survivin, see Altieri and Marchisio (1999).
Using flow cytometric analysis, Tao et al. (2005) found that NKT cells from patients with active systemic lupus erythematosus (SLE; 152700) were more susceptible to apoptosis induced by anti-CD95 (TNFRSF6; 134637) than NKT cells from patients with inactive SLE or normal controls. Further analysis suggested that deficient expression of CD226 (605397) and survivin in NKT cells from patients with active SLE may explain the sensitivity of these cells to apoptosis. However, in 2012, Tao et al. (2005) retracted their paper.
Adida, C., Crotty, P. L., McGrath, J., Berrebi, D., Diebold, J., Altieri, D. C.Developmentally regulated expression of the novel cancer anti-apoptosis gene survivin in human and mouse differentiation. Am. J. Path. 152: 43-49, 1998. [PubMed: 9422522]
Adida, C., Haioun, C., Gaulard, P., Lepage, E., Morel, P., Briere, J., Dombret, H., Reyes, F., Diebold, J., Gisselbrecht, C., Salles, G., Altieri, D. C., Molina, T. J.Prognostic significance of survivin expression in diffuse large B-cell lymphomas. Blood 96: 1921-1925, 2000. [PubMed: 10961895]
Altieri, D. C., Marchisio, P. C.Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab. Invest. 79: 1327-1333, 1999. Note: Erratum: Lab. Invest. 79: 1543 only, 1999. [PubMed: 10576203]
Ambrosini, G., Adida, C., Altieri, D. C.A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nature Med. 3: 917-921, 1997. [PubMed: 9256286] [Full Text: https://doi.org/10.1038/nm0897-917]
Ambrosini, G., Adida, C., Sirugo, G., Altieri, D. C.Induction of apoptosis and inhibition of cell proliferation by survivin gene targeting. J. Biol. Chem. 273: 11177-11182, 1998. [PubMed: 9556606] [Full Text: https://doi.org/10.1074/jbc.273.18.11177]
Asanuma, K., Tsuji, N., Endoh, T., Yagihashi, A., Watanabe, N.Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells. J. Immun. 172: 3922-3929, 2004. [PubMed: 15004200] [Full Text: https://doi.org/10.4049/jimmunol.172.6.3922]
Blanc-Brude, O. P., Yu, J., Simosa, H., Conte, M. S., Sessa, W. C., Altieri, D. C.Inhibitor of apoptosis protein survivin regulates vascular injury. Nature Med. 8: 987-994, 2002. [PubMed: 12172543] [Full Text: https://doi.org/10.1038/nm750]
Caldas, H., Holloway, M. P., Hall, B. M., Qualman, S. J., Altura, R. A.Survivin-directed RNA interference cocktail is a potent suppressor of tumour growth in vivo. J. Med. Genet. 43: 119-128, 2006. Note: Erratum: J. Med. Genet. 43: 418 only, 2006. [PubMed: 15908567] [Full Text: https://doi.org/10.1136/jmg.2005.034686]
Chantalat, L., Skoufias, D. A., Kleman, J.-P., Jung, B., Dideberg, O., Margolis, R. L.Crystal structure of human survivin reveals a bow tie-shaped dimer with two unusual alpha-helical extensions. Molec. Cell 6: 183-189, 2000. [PubMed: 10949039]
Dohi, T., Xia, F., Altieri, D. C.Compartmentalized phosphorylation of IAP by protein kinase A regulates cytoprotection. Molec. Cell 27: 17-28, 2007. [PubMed: 17612487] [Full Text: https://doi.org/10.1016/j.molcel.2007.06.004]
Esteve, P.-O., Chin, H. G., Pradhan, S.Human maintenance DNA (cytosine-5)-methyltransferase and p53 modulate expression of p53-repressed promoters. Proc. Nat. Acad. Sci. 102: 1000-1005, 2005. [PubMed: 15657147] [Full Text: https://doi.org/10.1073/pnas.0407729102]
Grossman, D., Kim, P. J., Schechner, J. S., Altieri, D. C.Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc. Nat. Acad. Sci. 98: 635-640, 2001. [PubMed: 11149963] [Full Text: https://doi.org/10.1073/pnas.98.2.635]
Gurbuxani, S., Xu, Y., Keerthivasan, G., Wickrema, A., Crispino, J. D.Differential requirements for survivin in hematopoietic cell development. Proc. Nat. Acad. Sci. 102: 11480-11485, 2005. [PubMed: 16055565] [Full Text: https://doi.org/10.1073/pnas.0500303102]
Kelly, A. E., Ghenoiu, C., Xue, J. Z., Zierhut, C., Kimura, H., Funabiki, H.Survivin reads phosphorylated histone H3 threonine 3 to activate the mitotic kinase Aurora B. Science 330: 235-239, 2010. [PubMed: 20705815] [Full Text: https://doi.org/10.1126/science.1189505]
Li, F., Ambrosini, G., Chu, E. Y., Plescia, J., Tognin, S., Marchisio, P. C., Altieri, D. C.Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396: 580-584, 1998. [PubMed: 9859993] [Full Text: https://doi.org/10.1038/25141]
Marusawa, H., Matsuzawa, S., Welsh, K., Zou, H., Armstrong, R., Tamm, I., Reed, J. C.HBXIP functions as a cofactor of survivin in apoptosis suppression. EMBO J. 22: 2729-2740, 2003. [PubMed: 12773388] [Full Text: https://doi.org/10.1093/emboj/cdg263]
McMurtry, M. S., Archer, S. L., Altieri, D. C., Bonnet, S., Haromy, A., Harry, G., Bonnet, S., Puttagunta, L., Michelakis, E. D.Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J. Clin. Invest. 115: 1479-1491, 2005. [PubMed: 15931388] [Full Text: https://doi.org/10.1172/JCI23203]
Mirza, A., McGuirk, M., Hockenberry, T. N., Wu, Q., Ashar, H., Black, S., Wen, S. F., Wang, L., Kirschmeier, P., Bishop, W. R., Nielsen, L. L., Pickett, C. B., Liu, S.Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21: 2613-2622, 2002. [PubMed: 11965534] [Full Text: https://doi.org/10.1038/sj.onc.1205353]
Muchmore, S. W., Chen, J., Jakob, C., Zakula, D., Matayoshi, E. D., Wu, W., Zhang, H., Li, F., Ng, S.-C., Altieri, D. C.Crystal structure and mutagenic analysis of the inhibitor-of-apoptosis protein survivin. Molec. Cell 6: 173-182, 2000. [PubMed: 10949038]
Sharief, M. K., Semra, Y. K.Down-regulation of survivin expression in T lymphocytes after interferon beta-1a treatment in patients with multiple sclerosis. Arch. Neurol. 59: 1115-1121, 2002. [PubMed: 12117359] [Full Text: https://doi.org/10.1001/archneur.59.7.1115]
Shinozawa, I., Inokuchi, K., Wakabayashi, I., Dan, K.Disturbed expression of the anti-apoptosis gene, survivin, and EPR-1 in hematological malignancies. Leukemia Res. 24: 965-970, 2000. [PubMed: 11086180] [Full Text: https://doi.org/10.1016/s0145-2126(00)00065-5]
Smith, S. D., Wheeler, M. A., Plescia, J., Colberg, J. W., Weiss, R. M., Altieri, D. C.Urine detection of survivin and diagnosis of bladder cancer. JAMA 285: 324-328, 2001. [PubMed: 11176843] [Full Text: https://doi.org/10.1001/jama.285.3.324]
Speliotes, E. K., Uren, A., Vaux, D., Horvitz, H. R.The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Molec. Cell 6: 211-223, 2000. [PubMed: 10983970] [Full Text: https://doi.org/10.1016/s1097-2765(00)00023-x]
Tao, D., Shangwu, L., Qun, W., Yan, L., Wei, J., Junyan, L., Feili, G., Boquan, J., Jinquan, T.CD226 expression deficiency causes high sensitivity to apoptosis in NK T cells from patients with systemic lupus erythematosus. J. Immun. 174: 1281-1290, 2005. Note: Retraction: J. Immun. 188: 5800 only, 2012. [PubMed: 15661884] [Full Text: https://doi.org/10.4049/jimmunol.174.3.1281]
Ueda, M., Yamashita, Y., Takehara, M., Terai, Y., Kumagai, K., Ueki, K., Kanda, K., Yamaguchi, H., Akise, D., Hung, Y.-C., Ueki, M.Survivin gene expression in endometriosis. J. Clin. Endocr. Metab. 87: 3452-3459, 2002. [PubMed: 12107265] [Full Text: https://doi.org/10.1210/jcem.87.7.8682]
Vong, Q. P., Cao, K., Li, H. Y., Iglesias, P. A., Zheng, Y.Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 310: 1499-1504, 2005. [PubMed: 16322459] [Full Text: https://doi.org/10.1126/science.1120160]
Wang, R.-H., Zheng, Y., Kim, H.-S., Xu, X., Cao, L., Luhasen, T., Lee, M.-H., Xiao, C., Vassilopoulos, A., Chen, W., Gardner, K., Man, Y.-G., Hung, M.-C., Finkel, T., Deng, C.-X.Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Molec. Cell 32: 11-20, 2008. [PubMed: 18851829] [Full Text: https://doi.org/10.1016/j.molcel.2008.09.011]
Wurl, P., Kappler, M., Meye, A., Bartel, F., Kohler, T., Lautenschlager, C., Bache, M., Schmidt, H., Taubert, H.Co-expression of survivin and TERT and risk of tumour-related death in patients with soft-tissue sarcoma. Lancet 359: 943-945, 2002. [PubMed: 11918915] [Full Text: https://doi.org/10.1016/S0140-6736(02)07990-4]
Yamagishi, Y., Honda, T., Tanno, Y., Watanabe, Y.Two histone marks establish the inner centromere and chromosome bi-orientation. Science 330: 239-233, 2010. [PubMed: 20929775] [Full Text: https://doi.org/10.1126/science.1194498]
Yamamoto, T., Manome, Y., Nakamura, M., Tanigawa, N.Downregulation of survivin expression by induction of the effector cell protease receptor-1 reduces tumor growth potential and results in an increased sensitivity to anticancer agents in human colon cancer. Europ. J. Cancer 38: 2316-2324, 2002. [PubMed: 12441269] [Full Text: https://doi.org/10.1016/s0959-8049(02)00247-2]
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