HGNC Approved Gene Symbol:CDKN2B
Cytogenetic location:9p21.3 Genomic coordinates(GRCh38) :9:22,002,903-22,009,313 (from NCBI)
Transforming growth factor-beta (TGFB;190180) inhibits cell proliferation by inducing a G1-phase cell cycle arrest. Normal progression through G1 is promoted by the activity of the cyclin-dependent protein kinases CDK4 (123829) and CDK6, which are inhibited by the protein p16(INK4) (CDKN2A;600160).Hannon and Beach (1994) isolated another member of the p16(INK4) family, which they referred to as p15(INK4B) or p15. The expression of this protein (CDKN2B) was induced approximately 30-fold in human keratinocytes by treatment with TGF-beta, suggesting that p15 may act as an effector of TGFB-mediated cell cycle arrest. Comparison of the sequence of the gene encoding p15(INK4B) with that reported for MTS2 (Kamb et al., 1994) demonstrated that the MTS2 sequence encodes the C-terminal 86 amino acids of p15(INK4B). MTS2 was found byKamb et al. (1994) to lie adjacent to the p16 gene (CDKN2) at 9p21, andHannon and Beach (1994) cited unpublished work localizing the p15 gene to that position by fluorescence in situ hybridization. Although a fragment of the p15 gene described byKamb et al. (1994) had been designated MTS2 (for multiple tumor suppressor-2),Hannon and Beach (1994) favored the name INK4B for 'inhibitor of CDK4-B.'
Using RT-PCR,Burdon et al. (2011) demonstrated expression of CDKN2A in human ocular tissues, including in the iris, ciliary body, retina, and optic nerve.
The p15(INK4b) gene is located adjacent to p16(INK4a) on 9p21 and is codeleted in a high proportion of established human cancer cell lines (Kamb et al., 1994;Nobori et al., 1994;Hannon and Beach, 1994).Okuda et al. (1995) used interphase fluorescence in situ hybridization, Southern blot analysis, and PCR to analyze the tandemly linked MTS1 (600160) and MTS2 loci in primary leukemic blasts from 43 pediatric patients with newly diagnosed acute lymphoblastic leukemia (ALL). Deletions were identified of 18 of 20 cases with cytogenetically observed abnormalities of 9p and in 5 of 23 cases with apparently normal chromosomes, with the majority containing biallelic deletions (16 homozygous and 7 hemizygous).
Quelle et al. (1995) mapped both the p16 and the p15 gene to mouse chromosome 4 in the C3-C6 region, which is syntenic with human 9p.
Cytogenetic abnormalities at 9p21 are common in many types of human tumors. The presence of 2 functional members of the p16 family at 9p21 raises the possibility that loss of tumor suppression may involve inactivation of either or both genes (Hannon and Beach, 1994). Deletions of 9p21 that remove both genes (or other mutations that might inactivate both) could simultaneously negate 2 major proliferation control pathways.
Stone et al. (1995) reported the genomic structure of p15 and its pattern of mRNA expression. They showed that ectopic expression of p15 inhibits growth of tumor-derived cell lines. In a search for p15 mutations in tumor cells lines and in 9p21-linked melanoma kindreds, they found, other than the previously described homozygous deletions, no mutations of p15. Collectively, they deduced from these observations that p15 has a role in growth regulation but a limited role in tumor progression.
Yu et al. (2008) demonstrated that many tumor suppressor genes have nearby antisense RNAs and focused on the role of one RNA in silencing p15, a cyclin-dependent kinase inhibitor implicated in leukemia.Yu et al. (2008) found an inverse relationship between p15-antisense (p15AS; see CDKN2BAS,613149) and p15 sense expression in leukemia. A p15AS expression construct induced p15 silencing in cis and in trans through heterochromatin formation but not DNA methylation; the silencing persisted after p15AS was turned off, although methylation and heterochromatin inhibitors reversed this process. The p15AS-induced silencing was Dicer-independent. Expression of exogenous p15AS in mouse embryonic stem cells caused p15 silencing and increased growth, through heterochromatin formation, as well as DNA methylation after differentiation of the embryonic stem cells. Thus,Yu et al. (2008) concluded that natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in tumor suppressor gene silencing in tumorigenesis.
Li et al. (2009) showed that the Ink4/Arf locus, comprising Cdkn2a (600160)-Cdnk2b, is completely silenced in induced pluripotent stem (iPS) cells as well as in embryonic stem cells, acquiring the epigenetic marks of a bivalent chromatin domain, and retaining the ability to be reactivated after differentiation. Cell culture conditions during reprogramming enhance the expression of the Ink4/Arf locus, further highlighting the importance of silencing the locus to allow proliferation and reprogramming. Indeed, Oct4 (164177), Klf4 (602253), and Sox2 (184429) together repress the Ink4/Arf locus soon after their expression and concomitant with the appearance of the first molecular markers of 'stemness.' This downregulation also occurs in cells carrying the oncoprotein simian virus-40 'large-T' antigen, which functionally inactivates the pathways regulated by the Ink4/Arf locus, thus indicating that the silencing of the locus is intrinsic to reprogramming and not the result of a selective process. Genetic inhibition of the Ink4/Arf locus has a profound positive effect on the efficiency of iPS cell generation, increasing both the kinetics of reprogramming and the number of emerging iPS cell colonies. In murine cells, Arf, rather than Ink4a, is the main barrier to reprogramming by activation of p53 (191170) and p21 (CDKN1A;116899), whereas in human fibroblasts, INK4a is more important than ARF. Furthermore, organismal aging upregulates the Ink4/Arf locus and, accordingly, reprogramming is less efficient in cells from old organisms, but this defect can be rescued by inhibiting the locus with a short hairpin RNA.Li et al. (2009) concluded that the silencing of Ink4/Arf locus is rate-limiting for reprogramming, and its transient inhibition may significantly improve the generation of iPS cells.
The myelodysplastic syndromes (MDS; see614286) comprise a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis with an increased propensity to acute myeloid leukemic transformation.Cameron et al. (2002) searched for mutations in the p15 gene in 5 MDS families (3 with multiple affected members in 2 successive generations and 2 with 1 generation of affected members) and found none.
In genomewide association studies of type 2 diabetes (125853) involving genotype data from a variety of international consortia, theDiabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007),Zeggini et al. (2007), andScott et al. (2007) detected association of a single-nucleotide polymorphism (SNP) on chromosome 9,rs10811661, and diabetes susceptibility. This SNP is 125 kb upstream from CDKN2A/CDKN2B, the nearest annotated genes. All-data metaanalyses obtained genomewide significance (OR = 1.20, P = 7.8 x 10(-15)).
Helgadottir et al. (2008) replicated the association of thers10811661 T allele to type 2 diabetes in Icelandic, Danish, and United States case-control groups (OR = 1.29, P = 2.5 x 10(-10)).
For discussion of a possible association between variation in the CDKN2B gene and susceptibility to glioma, see GLM5 (613030).
Krimpenfort et al. (2007) reported that mice deficient for all 3 open reading frames encoded at the Cdkn2 locus (Cdkn2ab-null) are more tumor-prone and develop a wider spectrum of tumors than Cdkn2a (600160) mutant mice, with a preponderance of skin tumors and soft tissue sarcomas (i.e., mesothelioma) frequently composed of mixed cell types and often showing biphasic differentiation. Cdkn2ab-null mouse embryonic fibroblasts were substantially more sensitive to oncogenic transformation than Cdkn2a mutant mouse embryonic fibroblasts. Under conditions of stress, p15(Ink4b) protein levels were significantly elevated in mouse embryonic fibroblasts deficient for p16(Ink4a).Krimpenfort et al. (2007) concluded that p15(Ink4b) can fulfill a critical backup function for p16(Ink4a) and suggested a model that provided an explanation for the frequent loss of the complete CDKN2B-CDKN2A locus in human tumors.
Visel et al. (2010) showed that deletion of the 70-kb noncoding interval on mouse chromosome 4 orthologous to the chromosome 9p21 interval associated with human coronary artery disease (CAD) (see CHD8,611139) affects cardiac expression of neighboring genes, as well as proliferation properties of vascular cells. Mice with homozygous deletion of the 70-kb interval (delta-70-kb) were viable but showed increased mortality both during development and as adults. Cardiac expression of 2 genes near the noncoding interval, Cdkn2a (600160) and Cdkn2b, was severely reduced in delta-70-kb homozygous mice, indicating that distant-acting gene regulatory functions are located in the noncoding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of aortic smooth muscle cells from homozygous delta-70-kb mice exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis.Visel et al. (2010) concluded that, taken together, their results provided direct evidence that the CAD risk interval has a pivotal role in the regulation of cardiac CDKN2A/B expression, and suggested that this region affects coronary artery disease progression by altering the dynamics of vascular cell proliferation.
Burdon, K. P., Macgregor, S., Hewitt, A. W., Sharma, S., Chidlow, G., Mills, R. A., Danoy, P., Casson, R., Viswanathan, A. C., Liu, J. Z., Landers, J., Henders, A. K., and 13 others.Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nature Genet. 43: 574-578, 2011. [PubMed:21532571,related citations] [Full Text]
Cameron, E., Mijovic, A., Herman, J. G., Baylin, S. B., Pradhan, A., Mufti, G. J., Rassool, F. V.P15(INK4B) is not mutated in adult familial myelodysplastic syndromes. (Letter) Brit. J. Haemat. 119: 277-279, 2002. [PubMed:12358941,related citations] [Full Text]
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research.Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316: 1331-1336, 2007. [PubMed:17463246,related citations] [Full Text]
Hannon, G. J., Beach, D.p15(INK4B) is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371: 257-261, 1994. [PubMed:8078588,related citations] [Full Text]
Helgadottir, A., Thorleifsson, G., Magnusson, K. P., Gretarsdottir, S., Steinthorsdottir, V., Manolescu, A., Jones, G. T., Rinkel, G. J. E., Blankensteijn, J. D., Ronkainen, A., Jaaskelainen, J. E., Kyo, Y., and 56 others.The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nature Genet. 40: 217-224, 2008. [PubMed:18176561,related citations] [Full Text]
Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, R. S., III, Johnson, B. E., Skolnick, M. H.A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436-440, 1994. [PubMed:8153634,related citations] [Full Text]
Krimpenfort, P., IJpenberg, A., Song, J.-Y., van der Valk, M., Nawijn, M., Zevenhoven, J., Berns, A.p15(Ink4b) is a critical tumour suppressor in the absence of p16(Ink4a). Nature 448: 943-946, 2007. [PubMed:17713536,related citations] [Full Text]
Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Canamero, M., Blasco, M. A., Serrano, M.The Ink4/Arf locus is a barrier for the iPS cell reprogramming. Nature 460: 1136-1139, 2009. [PubMed:19668188,images,related citations] [Full Text]
Nobori, T., Miura, K., Wu, D. J., Lois, A., Takabayashi, K., Carson, D. A.Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368: 753-756, 1994. [PubMed:8152487,related citations] [Full Text]
Okuda, T., Shurtleff, S. A., Valentine, M. B., Raimondi, S. C., Head, D. R., Behm, F., Curcio-Brint, A. M., Liu, Q., Pui, C.-H., Sherr, C. J., Beach, D., Look, A. T., Downing, J. R.Frequent deletion of p16(INK4a)/MTS1 and p15(INK4b)/MTS2 in pediatric acute lymphoblastic leukemia. Blood 85: 2321-2330, 1995. [PubMed:7727766,related citations]
Quelle, D. E., Ashmun, R. A., Hannon, G. J., Rehberger, P. A., Trono, D., Richter, K. H., Walker, C., Beach, D., Sherr, C. J., Serrano, M.Cloning and characterization of murine p16(INK4a) and p15(INK4b) genes. Oncogene 11: 635-645, 1995. [PubMed:7651726,related citations]
Scott, L. J., Mohlke, K. L., Bonnycastle, L. L., Willer, C. J., Li, Y., Duren, W. L., Erdos, M. R., Stringham, H. M., Chines, P. S., Jackson, A. U., Prokunina-Olsson, L., Ding, C.-J., and 29 others.A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341-1345, 2007. [PubMed:17463248,images,related citations] [Full Text]
Stone, S., Dayananth, P., Jiang, P., Weaver-Feldhaus, J. M., Tavtigian, S. V., Cannon-Albright, L., Kamb, A.Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. Oncogene 11: 987-991, 1995. [PubMed:7675459,related citations]
Visel, A., Zhu, Y., May, D., Afzal, V., Gong, E., Attanasio, C., Blow, M. J., Cohen, J. C., Rubin, E. M., Pennacchio, L. A.Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464: 409-412, 2010. [PubMed:20173736,images,related citations] [Full Text]
Yu, W., Gius, D., Onyango, P., Muldoon-Jacobs, K., Karp, J., Feinberg, A. P., Cui, H.Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451: 202-206, 2008. [PubMed:18185590,images,related citations] [Full Text]
Zeggini, E., Weedon, M. N., Lindgren, C. M., Frayling, T. M., Elliott, K. S., Lango, H., Timpson, N. J., Perry, J. R. B., Rayner, N. W., Freathy, R. M., Barrett, J. C., Shields, B., and 15 others.Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336-1341, 2007. Note: Erratum: Science 317: 1036 only, 2007. [PubMed:17463249,images,related citations] [Full Text]
Alternative titles; symbols
HGNC Approved Gene Symbol: CDKN2B
Cytogenetic location: 9p21.3 Genomic coordinates(GRCh38) : 9:22,002,903-22,009,313(from NCBI)
Transforming growth factor-beta (TGFB; 190180) inhibits cell proliferation by inducing a G1-phase cell cycle arrest. Normal progression through G1 is promoted by the activity of the cyclin-dependent protein kinases CDK4 (123829) and CDK6, which are inhibited by the protein p16(INK4) (CDKN2A; 600160). Hannon and Beach (1994) isolated another member of the p16(INK4) family, which they referred to as p15(INK4B) or p15. The expression of this protein (CDKN2B) was induced approximately 30-fold in human keratinocytes by treatment with TGF-beta, suggesting that p15 may act as an effector of TGFB-mediated cell cycle arrest. Comparison of the sequence of the gene encoding p15(INK4B) with that reported for MTS2 (Kamb et al., 1994) demonstrated that the MTS2 sequence encodes the C-terminal 86 amino acids of p15(INK4B). MTS2 was found by Kamb et al. (1994) to lie adjacent to the p16 gene (CDKN2) at 9p21, and Hannon and Beach (1994) cited unpublished work localizing the p15 gene to that position by fluorescence in situ hybridization. Although a fragment of the p15 gene described by Kamb et al. (1994) had been designated MTS2 (for multiple tumor suppressor-2), Hannon and Beach (1994) favored the name INK4B for 'inhibitor of CDK4-B.'
Using RT-PCR, Burdon et al. (2011) demonstrated expression of CDKN2A in human ocular tissues, including in the iris, ciliary body, retina, and optic nerve.
The p15(INK4b) gene is located adjacent to p16(INK4a) on 9p21 and is codeleted in a high proportion of established human cancer cell lines (Kamb et al., 1994; Nobori et al., 1994; Hannon and Beach, 1994). Okuda et al. (1995) used interphase fluorescence in situ hybridization, Southern blot analysis, and PCR to analyze the tandemly linked MTS1 (600160) and MTS2 loci in primary leukemic blasts from 43 pediatric patients with newly diagnosed acute lymphoblastic leukemia (ALL). Deletions were identified of 18 of 20 cases with cytogenetically observed abnormalities of 9p and in 5 of 23 cases with apparently normal chromosomes, with the majority containing biallelic deletions (16 homozygous and 7 hemizygous).
Quelle et al. (1995) mapped both the p16 and the p15 gene to mouse chromosome 4 in the C3-C6 region, which is syntenic with human 9p.
Cytogenetic abnormalities at 9p21 are common in many types of human tumors. The presence of 2 functional members of the p16 family at 9p21 raises the possibility that loss of tumor suppression may involve inactivation of either or both genes (Hannon and Beach, 1994). Deletions of 9p21 that remove both genes (or other mutations that might inactivate both) could simultaneously negate 2 major proliferation control pathways.
Stone et al. (1995) reported the genomic structure of p15 and its pattern of mRNA expression. They showed that ectopic expression of p15 inhibits growth of tumor-derived cell lines. In a search for p15 mutations in tumor cells lines and in 9p21-linked melanoma kindreds, they found, other than the previously described homozygous deletions, no mutations of p15. Collectively, they deduced from these observations that p15 has a role in growth regulation but a limited role in tumor progression.
Yu et al. (2008) demonstrated that many tumor suppressor genes have nearby antisense RNAs and focused on the role of one RNA in silencing p15, a cyclin-dependent kinase inhibitor implicated in leukemia. Yu et al. (2008) found an inverse relationship between p15-antisense (p15AS; see CDKN2BAS, 613149) and p15 sense expression in leukemia. A p15AS expression construct induced p15 silencing in cis and in trans through heterochromatin formation but not DNA methylation; the silencing persisted after p15AS was turned off, although methylation and heterochromatin inhibitors reversed this process. The p15AS-induced silencing was Dicer-independent. Expression of exogenous p15AS in mouse embryonic stem cells caused p15 silencing and increased growth, through heterochromatin formation, as well as DNA methylation after differentiation of the embryonic stem cells. Thus, Yu et al. (2008) concluded that natural antisense RNA may be a trigger for heterochromatin formation and DNA methylation in tumor suppressor gene silencing in tumorigenesis.
Li et al. (2009) showed that the Ink4/Arf locus, comprising Cdkn2a (600160)-Cdnk2b, is completely silenced in induced pluripotent stem (iPS) cells as well as in embryonic stem cells, acquiring the epigenetic marks of a bivalent chromatin domain, and retaining the ability to be reactivated after differentiation. Cell culture conditions during reprogramming enhance the expression of the Ink4/Arf locus, further highlighting the importance of silencing the locus to allow proliferation and reprogramming. Indeed, Oct4 (164177), Klf4 (602253), and Sox2 (184429) together repress the Ink4/Arf locus soon after their expression and concomitant with the appearance of the first molecular markers of 'stemness.' This downregulation also occurs in cells carrying the oncoprotein simian virus-40 'large-T' antigen, which functionally inactivates the pathways regulated by the Ink4/Arf locus, thus indicating that the silencing of the locus is intrinsic to reprogramming and not the result of a selective process. Genetic inhibition of the Ink4/Arf locus has a profound positive effect on the efficiency of iPS cell generation, increasing both the kinetics of reprogramming and the number of emerging iPS cell colonies. In murine cells, Arf, rather than Ink4a, is the main barrier to reprogramming by activation of p53 (191170) and p21 (CDKN1A; 116899), whereas in human fibroblasts, INK4a is more important than ARF. Furthermore, organismal aging upregulates the Ink4/Arf locus and, accordingly, reprogramming is less efficient in cells from old organisms, but this defect can be rescued by inhibiting the locus with a short hairpin RNA. Li et al. (2009) concluded that the silencing of Ink4/Arf locus is rate-limiting for reprogramming, and its transient inhibition may significantly improve the generation of iPS cells.
The myelodysplastic syndromes (MDS; see 614286) comprise a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis with an increased propensity to acute myeloid leukemic transformation. Cameron et al. (2002) searched for mutations in the p15 gene in 5 MDS families (3 with multiple affected members in 2 successive generations and 2 with 1 generation of affected members) and found none.
In genomewide association studies of type 2 diabetes (125853) involving genotype data from a variety of international consortia, the Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research (2007), Zeggini et al. (2007), and Scott et al. (2007) detected association of a single-nucleotide polymorphism (SNP) on chromosome 9, rs10811661, and diabetes susceptibility. This SNP is 125 kb upstream from CDKN2A/CDKN2B, the nearest annotated genes. All-data metaanalyses obtained genomewide significance (OR = 1.20, P = 7.8 x 10(-15)).
Helgadottir et al. (2008) replicated the association of the rs10811661 T allele to type 2 diabetes in Icelandic, Danish, and United States case-control groups (OR = 1.29, P = 2.5 x 10(-10)).
For discussion of a possible association between variation in the CDKN2B gene and susceptibility to glioma, see GLM5 (613030).
Krimpenfort et al. (2007) reported that mice deficient for all 3 open reading frames encoded at the Cdkn2 locus (Cdkn2ab-null) are more tumor-prone and develop a wider spectrum of tumors than Cdkn2a (600160) mutant mice, with a preponderance of skin tumors and soft tissue sarcomas (i.e., mesothelioma) frequently composed of mixed cell types and often showing biphasic differentiation. Cdkn2ab-null mouse embryonic fibroblasts were substantially more sensitive to oncogenic transformation than Cdkn2a mutant mouse embryonic fibroblasts. Under conditions of stress, p15(Ink4b) protein levels were significantly elevated in mouse embryonic fibroblasts deficient for p16(Ink4a). Krimpenfort et al. (2007) concluded that p15(Ink4b) can fulfill a critical backup function for p16(Ink4a) and suggested a model that provided an explanation for the frequent loss of the complete CDKN2B-CDKN2A locus in human tumors.
Visel et al. (2010) showed that deletion of the 70-kb noncoding interval on mouse chromosome 4 orthologous to the chromosome 9p21 interval associated with human coronary artery disease (CAD) (see CHD8, 611139) affects cardiac expression of neighboring genes, as well as proliferation properties of vascular cells. Mice with homozygous deletion of the 70-kb interval (delta-70-kb) were viable but showed increased mortality both during development and as adults. Cardiac expression of 2 genes near the noncoding interval, Cdkn2a (600160) and Cdkn2b, was severely reduced in delta-70-kb homozygous mice, indicating that distant-acting gene regulatory functions are located in the noncoding CAD risk interval. Allele-specific expression of Cdkn2b transcripts in heterozygous mice showed that the deletion affects expression through a cis-acting mechanism. Primary cultures of aortic smooth muscle cells from homozygous delta-70-kb mice exhibited excessive proliferation and diminished senescence, a cellular phenotype consistent with accelerated CAD pathogenesis. Visel et al. (2010) concluded that, taken together, their results provided direct evidence that the CAD risk interval has a pivotal role in the regulation of cardiac CDKN2A/B expression, and suggested that this region affects coronary artery disease progression by altering the dynamics of vascular cell proliferation.
Burdon, K. P., Macgregor, S., Hewitt, A. W., Sharma, S., Chidlow, G., Mills, R. A., Danoy, P., Casson, R., Viswanathan, A. C., Liu, J. Z., Landers, J., Henders, A. K., and 13 others.Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nature Genet. 43: 574-578, 2011. [PubMed: 21532571] [Full Text: https://doi.org/10.1038/ng.824]
Cameron, E., Mijovic, A., Herman, J. G., Baylin, S. B., Pradhan, A., Mufti, G. J., Rassool, F. V.P15(INK4B) is not mutated in adult familial myelodysplastic syndromes. (Letter) Brit. J. Haemat. 119: 277-279, 2002. [PubMed: 12358941] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.37707.x]
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes for BioMedical Research.Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316: 1331-1336, 2007. [PubMed: 17463246] [Full Text: https://doi.org/10.1126/science.1142358]
Hannon, G. J., Beach, D.p15(INK4B) is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371: 257-261, 1994. [PubMed: 8078588] [Full Text: https://doi.org/10.1038/371257a0]
Helgadottir, A., Thorleifsson, G., Magnusson, K. P., Gretarsdottir, S., Steinthorsdottir, V., Manolescu, A., Jones, G. T., Rinkel, G. J. E., Blankensteijn, J. D., Ronkainen, A., Jaaskelainen, J. E., Kyo, Y., and 56 others.The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm. Nature Genet. 40: 217-224, 2008. [PubMed: 18176561] [Full Text: https://doi.org/10.1038/ng.72]
Kamb, A., Gruis, N. A., Weaver-Feldhaus, J., Liu, Q., Harshman, K., Tavtigian, S. V., Stockert, E., Day, R. S., III, Johnson, B. E., Skolnick, M. H.A cell cycle regulator potentially involved in genesis of many tumor types. Science 264: 436-440, 1994. [PubMed: 8153634] [Full Text: https://doi.org/10.1126/science.8153634]
Krimpenfort, P., IJpenberg, A., Song, J.-Y., van der Valk, M., Nawijn, M., Zevenhoven, J., Berns, A.p15(Ink4b) is a critical tumour suppressor in the absence of p16(Ink4a). Nature 448: 943-946, 2007. [PubMed: 17713536] [Full Text: https://doi.org/10.1038/nature06084]
Li, H., Collado, M., Villasante, A., Strati, K., Ortega, S., Canamero, M., Blasco, M. A., Serrano, M.The Ink4/Arf locus is a barrier for the iPS cell reprogramming. Nature 460: 1136-1139, 2009. [PubMed: 19668188] [Full Text: https://doi.org/10.1038/nature08290]
Nobori, T., Miura, K., Wu, D. J., Lois, A., Takabayashi, K., Carson, D. A.Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368: 753-756, 1994. [PubMed: 8152487] [Full Text: https://doi.org/10.1038/368753a0]
Okuda, T., Shurtleff, S. A., Valentine, M. B., Raimondi, S. C., Head, D. R., Behm, F., Curcio-Brint, A. M., Liu, Q., Pui, C.-H., Sherr, C. J., Beach, D., Look, A. T., Downing, J. R.Frequent deletion of p16(INK4a)/MTS1 and p15(INK4b)/MTS2 in pediatric acute lymphoblastic leukemia. Blood 85: 2321-2330, 1995. [PubMed: 7727766]
Quelle, D. E., Ashmun, R. A., Hannon, G. J., Rehberger, P. A., Trono, D., Richter, K. H., Walker, C., Beach, D., Sherr, C. J., Serrano, M.Cloning and characterization of murine p16(INK4a) and p15(INK4b) genes. Oncogene 11: 635-645, 1995. [PubMed: 7651726]
Scott, L. J., Mohlke, K. L., Bonnycastle, L. L., Willer, C. J., Li, Y., Duren, W. L., Erdos, M. R., Stringham, H. M., Chines, P. S., Jackson, A. U., Prokunina-Olsson, L., Ding, C.-J., and 29 others.A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316: 1341-1345, 2007. [PubMed: 17463248] [Full Text: https://doi.org/10.1126/science.1142382]
Stone, S., Dayananth, P., Jiang, P., Weaver-Feldhaus, J. M., Tavtigian, S. V., Cannon-Albright, L., Kamb, A.Genomic structure, expression and mutational analysis of the P15 (MTS2) gene. Oncogene 11: 987-991, 1995. [PubMed: 7675459]
Visel, A., Zhu, Y., May, D., Afzal, V., Gong, E., Attanasio, C., Blow, M. J., Cohen, J. C., Rubin, E. M., Pennacchio, L. A.Targeted deletion of the 9p21 non-coding coronary artery disease risk interval in mice. Nature 464: 409-412, 2010. [PubMed: 20173736] [Full Text: https://doi.org/10.1038/nature08801]
Yu, W., Gius, D., Onyango, P., Muldoon-Jacobs, K., Karp, J., Feinberg, A. P., Cui, H.Epigenetic silencing of tumour suppressor gene p15 by its antisense RNA. Nature 451: 202-206, 2008. [PubMed: 18185590] [Full Text: https://doi.org/10.1038/nature06468]
Zeggini, E., Weedon, M. N., Lindgren, C. M., Frayling, T. M., Elliott, K. S., Lango, H., Timpson, N. J., Perry, J. R. B., Rayner, N. W., Freathy, R. M., Barrett, J. C., Shields, B., and 15 others.Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316: 1336-1341, 2007. Note: Erratum: Science 317: 1036 only, 2007. [PubMed: 17463249] [Full Text: https://doi.org/10.1126/science.1142364]
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