Proto-oncogene serine/threonine-protein kinase Pim-1 is anenzyme that in humans is encoded by thePIM1gene.[5][6][7]
Pim-1 is aproto-oncogene which encodes for theserine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murineT-cell lymphomas, as it was the locus most frequently activated by the Moloneymurine leukemia virus.[8] Subsequently, the oncogene has been implicated in multiple human cancers, includingprostate cancer,acute myeloid leukemia and otherhematopoietic malignancies.[9] Primarily expressed in spleen, thymus, bone marrow, prostate, oralepithelial,hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed incell cultures isolated from human tumors.[8] Pim-1 is mainly involved incell cycle progression,apoptosis andtranscriptional activation, as well as more generalsignal transduction pathways.[8] Pim-1's role in oncogenic signalling has led to it becoming a widely studied target in cancer research, with numerous drug candidates under investigation which target it.[10][11]
Located on chromosome 6 (6p21.2), the gene encompasses 5Kb of DNA, including 6 exons and 5 introns. Expression of Pim-1 has been shown to be regulated by theJAK/STAT pathway. Direct binding of transcription factorsSTAT3 andSTAT5 to the Pim-1promoter results in the transcription of Pim-1.[8] The Pim-1 gene has been found to be conserved in dogs, cows, mice, rats, zebrafish andC. elegans. Pim-1 deficient mice have been shown to be phenotypically normal, indicating that there is redundancy in the function of this kinase.[8] In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar.[8] The Pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD.[8]
Human, murine and rat Pim-1 contain 313 amino acids, and have a 94 – 97% amino acid identity.[8] The active site of the protein, ranging from amino acids 38-290, is composed of several conserved motifs, including a glycine loop motif, a phosphate binding site and a proton acceptor site.[8] Modification of the protein at amino acid 67 (lysine to methionine) results in the inactivation of the kinase.[8]
Pim-1 is primarily involved incytokine signaling, and has been implicated in manysignal transduction pathways. Because Pim-1 transcription is initiated by STAT3 and STAT5, its production is regulated by the cytokines that regulate the STAT pathway, or STAT factors. These includeinterleukins (IL-2, IL-3, IL-5, IL-6, IL-7, IL12, IL-15), prolactin,TNFα,EGF andIFNγ, among others.[8] Pim-1 itself can bind to negative regulators of the JAK/STAT pathway, resulting in a negative feedback loop.
Although little is known about the post-transcriptional modifications of Pim-1, it has been hypothesized thatHsp90 is responsible for the folding and stabilization of Pim-1, although the exact mechanism has yet to be discovered.[8] Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1.
Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor proteinp100,HP-1,PAP-1 andTRAF2 /SNX6), and regulation of the JAK/STAT pathway (SOCS1 andSOCS3).[8] Furthermore, Pim-1 has been shown to be a cofactor forc-Myc, atranscription factor believed to regulate 15% of all genes, and their synergy has been in prostate tumorigenesis.[20]
Pim-1 is able to phosphorylate many targets, including itself. Many of its targets are involved incell cycle regulation.
Pim-1 is directly involved in the regulation of cell cycle progression and apoptosis, and has been implicated in numerous cancers including prostate cancer, Burkitt's lymphoma and oral cancer, as well as numerous hematopoietic lymphomas. Single nucleotide polymorphisms in the Pim-1 gene have been associated with increased risk for lung cancer in Korean patients, and have also been found in diffuse large cell lymphomas.[21] As well as showing useful activity against a range of cancers,[11] PIM kinase inhibitors have also been suggested as possible treatments forAlzheimer's disease.[22] PIM expression is sufficient to drive resistance to anti-angiogenic agents in prostate and colon cancer models, although the mechanism is not fully elucidated.[23] It has been suggested that a co-targeted therapeutic approach to inhibition of Pim-1 in cancer may be preferable, with suggested co-targets including the PI3K pathway and more.[10]PIM1 expression was found to be elevated during aging and to contribute to the development of pulmonary fibrosis.[24]
A large number of small molecule inhibitors of PIM1 have been developed. Clinical trial results so far[when?] have shown promising anti-cancer activity, but side effects due to insufficient selectivity have proved problematic and research continues to find more potent and selective inhibitors for this target.[25][26][27][28][29][30][31][10][11]
^Domen J, Von Lindern M, Hermans A, et al. (June 1987). "Comparison of the human and mouse PIM-1 cDNAs: nucleotide sequence and immunological identification of the in vitro synthesized PIM-1 protein".Oncogene Research.1 (1):103–12.PMID3329709.
^Meeker TC, Nagarajan L, ar-Rushdi A, et al. (June 1987). "Characterization of the human PIM-1 gene: a putative proto-oncogene coding for a tissue specific member of the protein kinase family".Oncogene Research.1 (1):87–101.PMID3329711.
^Arunesh GM, Shanthi E, Krishna MH, et al. (January 2014). "Small molecule inhibitors of PIM1 kinase: July 2009 to February 2013 patent update".Expert Opinion on Therapeutic Patents.24 (1):5–17.doi:10.1517/13543776.2014.848196.PMID24131033.S2CID2331769.
^Burger MT, Nishiguchi G, Han W, et al. (November 2015). "Identification of N-(4-((1R,3S,5S)-3-Amino-5-methylcyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide (PIM447), a Potent and Selective Proviral Insertion Site of Moloney Murine Leukemia (PIM) 1, 2, and 3 Kinase Inhibitor in Clinical Trials for Hematological Malignancies".Journal of Medicinal Chemistry.58 (21):8373–86.doi:10.1021/acs.jmedchem.5b01275.PMID26505898.
Ragoussis J, Senger G, Mockridge I, et al. (November 1992). "A testis-expressed Zn finger gene (ZNF76) in human 6p21.3 centromeric to the MHC is closely linked to the human homolog of the t-complex gene tcp-11".Genomics.14 (3):673–9.doi:10.1016/S0888-7543(05)80167-3.PMID1427894.
Reeves R, Spies GA, Kiefer M, et al. (June 1990). "Primary structure of the putative human oncogene, pim-1".Gene.90 (2):303–7.doi:10.1016/0378-1119(90)90195-W.PMID2205533.
Meeker TC, Nagarajan L, ar-Rushdi A, et al. (October 1987). "Cloning and characterization of the human PIM-1 gene: a putative oncogene related to the protein kinases".Journal of Cellular Biochemistry.35 (2):105–12.doi:10.1002/jcb.240350204.PMID3429489.S2CID43495337.
Zakut-Houri R, Hazum S, Givol D, et al. (1987). "The cDNA sequence and gene analysis of the human pim oncogene".Gene.54 (1):105–11.doi:10.1016/0378-1119(87)90352-0.PMID3475233.
Wang Z, Bhattacharya N, Meyer MK, et al. (June 2001). "Pim-1 negatively regulates the activity of PTP-U2S phosphatase and influences terminal differentiation and apoptosis of monoblastoid leukemia cells".Archives of Biochemistry and Biophysics.390 (1):9–18.doi:10.1006/abbi.2001.2370.PMID11368509.
![1yxx: Crystal Structure of Kinase Pim1 in complex with (3E)-3-[(4-HYDROXYPHENYL)IMINO]-1H-INDOL-2(3H)-ONE](/mt/?noimg=&dark=on&url=http%3a%2f%2fen.wikipedia.org%2fwiki%2fFile%3aPDB_1yxx_EBI.png)
