PIM1 explained

Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the PIM1 gene.[1] [2] [3]

Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine T-cell lymphomas, as it was the locus most frequently activated by the Moloney murine leukemia virus.[4] Subsequently, the oncogene has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies.[5] Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in cell cultures isolated from human tumors.[4] Pim-1 is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways.[4] 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.[6] [7]

Gene

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 the JAK/STAT pathway. Direct binding of transcription factors STAT3 and STAT5 to the Pim-1 promoter results in the transcription of Pim-1.[4] The Pim-1 gene has been found to be conserved in dogs, cows, mice, rats, zebrafish and C. elegans. Pim-1 deficient mice have been shown to be phenotypically normal, indicating that there is redundancy in the function of this kinase.[4] In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar.[4] The Pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD.[4]

Protein structure

Human, murine and rat Pim-1 contain 313 amino acids, and have a 94 – 97% amino acid identity.[4] 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.[4] Modification of the protein at amino acid 67 (lysine to methionine) results in the inactivation of the kinase.[4]

Activation and stabilization

Pim-1 is primarily involved in cytokine signaling, and has been implicated in many signal 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 include interleukins (IL-2, IL-3,IL-5, IL-6, IL-7, IL12, IL-15), prolactin, TNFα, EGF and IFNγ, among others.[4] 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 that Hsp90 is responsible for the folding and stabilization of Pim-1, although the exact mechanism has yet to be discovered.[4] Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1.

Interactions

PIM1 has been shown to interact with:

Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor protein p100, HP-1, PAP-1 and TRAF2 / SNX6), and regulation of the JAK/STAT pathway (SOCS1 and SOCS3).[4] Furthermore, Pim-1 has been shown to be a cofactor for c-Myc, a transcription factor believed to regulate 15% of all genes, and their synergy has been in prostate tumorigenesis.[16]

Pim-1 is able to phosphorylate many targets, including itself. Many of its targets are involved in cell cycle regulation.

Activates

Deactivates

Clinical implications

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.[17] As well as showing useful activity against a range of cancers,[7] PIM kinase inhibitors have also been suggested as possible treatments for Alzheimer's disease.[18] PIM expression is sufficient to drive resistance to anti-angiogenic agents in prostate and colon cancer models, although the mechanism is not fully elucidated.[19] 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.[6] PIM1 expression was found to be elevated during aging and to contribute to the development of pulmonary fibrosis.[20]

Inhibitors

A large number of small molecule inhibitors of PIM1 have been developed. Clinical trial results so far have showed 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.[21] [22] [23] [24] [25] [26] [27] [6] [7]

Examples

Further reading

Notes and References

  1. Web site: Entrez Gene: PIM1 pim-1 oncogene.
  2. Domen J, Von Lindern M, Hermans A, Breuer M, Grosveld G, Berns A . 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 . June 1987 . 3329709 .
  3. Meeker TC, Nagarajan L, ar-Rushdi A, Rovera G, Huebner K, Croce CM . 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 . June 1987 . 3329711 .
  4. Bachmann M, Möröy T . The serine/threonine kinase Pim-1 . The International Journal of Biochemistry & Cell Biology . 37 . 4 . 726–30 . April 2005 . 15694833 . 10.1016/j.biocel.2004.11.005 .
  5. Web site: Pim-1 Oncogene. 2015-12-14 .
  6. Luszczak S, Kumar C, Sathyadevan VK, Simpson BS, Gately KA, Whitaker HC, Heavey S . PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer . Signal Transduction and Targeted Therapy . 5 . 7 . 2020 . 32025342 . 6992635 . 10.1038/s41392-020-0109-y .
  7. Malone T, Schäfer L, Simon N, Heavey S, Cuffe S, Finn S, Moore G, Gately K . Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer . Pharmacology & Therapeutics . 207 . 107454 . March 2020 . 31836451 . 10.1016/j.pharmthera.2019.107454 . 209357486 .
  8. Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM . Identification of heterochromatin protein 1 (HP1) as a phosphorylation target by Pim-1 kinase and the effect of phosphorylation on the transcriptional repression function of HP1(1) . FEBS Letters . 467 . 1 . 17–21 . February 2000 . 10664448 . 10.1016/S0014-5793(00)01105-4 . 29392124 . free .
  9. Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y . Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway . The Journal of Biological Chemistry . 274 . 26 . 18659–66 . June 1999 . 10373478 . 10.1074/jbc.274.26.18659 . free .
  10. Mizuno K, Shirogane T, Shinohara A, Iwamatsu A, Hibi M, Hirano T . Regulation of Pim-1 by Hsp90 . Biochemical and Biophysical Research Communications . 281 . 3 . 663–9 . March 2001 . 11237709 . 10.1006/bbrc.2001.4405 .
  11. Rainio EM, Sandholm J, Koskinen PJ . Cutting edge: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase . Journal of Immunology . 168 . 4 . 1524–7 . February 2002 . 11823475 . 10.4049/jimmunol.168.4.1524 . free .
  12. Bhattacharya N, Wang Z, Davitt C, McKenzie IF, Xing PX, Magnuson NS . Pim-1 associates with protein complexes necessary for mitosis . Chromosoma . 111 . 2 . 80–95 . July 2002 . 12111331 . 10.1007/s00412-002-0192-6 . 26016943 .
  13. Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS . Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1593 . 1 . 45–55 . December 2002 . 12431783 . 10.1016/S0167-4889(02)00347-6 . free .
  14. Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen KJ, Dash AB, Eisenman RN, Ness SA . Pim-1 kinase and p100 cooperate to enhance c-Myb activity . Molecular Cell . 2 . 4 . 417–25 . October 1998 . 9809063 . 10.1016/S1097-2765(00)80141-0 . free .
  15. Nihira K, Ando Y, Yamaguchi T, Kagami Y, Miki Y, Yoshida K . Pim-1 controls NF-kappaB signalling by stabilizing RelA/p65 . Cell Death and Differentiation . 17 . 4 . 689–98 . April 2010 . 19911008 . 10.1038/cdd.2009.174 . free .
  16. Wang J, Kim J, Roh M, Franco OE, Hayward SW, Wills ML, Abdulkadir SA . Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma . Oncogene . 29 . 17 . 2477–87 . April 2010 . 20140016 . 2861731 . 10.1038/onc.2010.10 .
  17. Kim DS, Sung JS, Shin ES, Ryu JS, Choi IK, Park KH, Park Y, Kim EB, Park SJ, Kim YH . Association of single nucleotide polymorphisms in PIM-1 gene with the risk of Korean lung cancer . Cancer Research and Treatment . 40 . 4 . 190–6 . December 2008 . 19688129 . 2697471 . 10.4143/crt.2008.40.4.190 .
  18. Velazquez R, Shaw DM, Caccamo A, Oddo S . Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease . Molecular Neurodegeneration . 11 . 1 . 52 . July 2016 . 27412291 . 10.1186/s13024-016-0118-z . 4944476 . free .
  19. Casillas AL, Toth RK, Sainz AG, Singh N, Desai AA, Kraft AS, Warfel NA . Hypoxia-Inducible PIM Kinase Expression Promotes Resistance to Antiangiogenic Agents . Clinical Cancer Research . 24 . 1 . 169–180 . 2018 . 29084916 . 10.1158/1078-0432.CCR-17-1318 . 6214353.
  20. Pham TX, Lee J, Guan J, Caporarello N, Meridew JA, Jones DL, Tan Q, Huang SK, Tschumperlin DJ, Ligresti G . Transcriptional analysis of lung fibroblasts identifies PIM1 signaling as a driver of aging-associated persistent fibrosis . JCI Insight . February 2022 . 7 . 6 . 35167499 . 10.1172/jci.insight.153672 . 8986080 .
  21. Morwick T . Pim kinase inhibitors: a survey of the patent literature . Expert Opinion on Therapeutic Patents . 20 . 2 . 193–212 . February 2010 . 20100002 . 10.1517/13543770903496442 . 19401237 .
  22. Merkel AL, Meggers E, Ocker M . PIM1 kinase as a target for cancer therapy . Expert Opinion on Investigational Drugs . 21 . 4 . 425–36 . April 2012 . 22385334 . 10.1517/13543784.2012.668527 . 26602099 .
  23. Foulks JM, Carpenter KJ, Luo B, Xu Y, Senina A, Nix R, Chan A, Clifford A, Wilkes M, Vollmer D, Brenning B, Merx S, Lai S, McCullar MV, Ho KK, Albertson DJ, Call LT, Bearss JJ, Tripp S, Liu T, Stephens BJ, Mollard A, Warner SL, Bearss DJ, Kanner SB . A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas . Neoplasia . 16 . 5 . 403–412 . May 2014 . 24953177 . 10.1016/j.neo.2014.05.004 . 4198696.
  24. Arunesh GM, Shanthi E, Krishna MH, Sooriya Kumar J, Viswanadhan VN . Small molecule inhibitors of PIM1 kinase: July 2009 to February 2013 patent update . Expert Opinion on Therapeutic Patents . 24 . 1 . 5–17 . January 2014 . 24131033 . 10.1517/13543776.2014.848196 . 2331769 .
  25. Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M . Targeting the Pim kinases in multiple myeloma . Blood Cancer Journal . 5 . e325 . July 2015 . 7 . 26186558 . 10.1038/bcj.2015.46 . 4526774.
  26. Le BT, Kumarasiri M, Adams JR, Yu M, Milne R, Sykes MJ, Wang S . Targeting Pim kinases for cancer treatment: opportunities and challenges . . 7 . 1 . 35–53 . 2015 . 25582332 . 10.4155/fmc.14.145 .
  27. Tursynbay Y, Zhang J, Li Z, Tokay T, Zhumadilov Z, Wu D, Xie Y . Pim-1 kinase as cancer drug target: An update . Biomedical Reports . 4 . 2 . 140–146 . February 2016 . 26893828 . 10.3892/br.2015.561 . 4734217.
  28. Keeton EK, McEachern K, Dillman KS, Palakurthi S, Cao Y, Grondine MR, Kaur S, Wang S, Chen Y, Wu A, Shen M, Gibbons FD, Lamb ML, Zheng X, Stone RM, Deangelo DJ, Platanias LC, Dakin LA, Chen H, Lyne PD, Huszar D . AZD1208, a potent and selective pan-Pim kinase inhibitor, demonstrates efficacy in preclinical models of acute myeloid leukemia . Blood . 123 . 6 . 905–13 . February 2014 . 24363397 . 10.1182/blood-2013-04-495366 . 3916880 . free .
  29. Burger MT, Nishiguchi G, Han W, Lan J, Simmons R, Atallah G, Ding Y, Tamez V, Zhang Y, Mathur M, Muller K, Bellamacina C, Lindvall MK, Zang R, Huh K, Feucht P, Zavorotinskaya T, Dai Y, Basham S, Chan J, Ginn E, Aycinena A, Holash J, Castillo J, Langowski JL, Wang Y, Chen MY, Lambert A, Fritsch C, Kauffmann A, Pfister E, Vanasse KG, Garcia PD . 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 . November 2015 . 26505898 . 10.1021/acs.jmedchem.5b01275 .
  30. Mumenthaler SM, Ng PY, Hodge A, Bearss D, Berk G, Kanekal S, Redkar S, Taverna P, Agus DB, Jain A . Pharmacologic inhibition of Pim kinases alters prostate cancer cell growth and resensitizes chemoresistant cells to taxanes . Molecular Cancer Therapeutics . 8 . 10 . 2882–93 . October 2009 . 19825806 . 10.1158/1535-7163.MCT-09-0293 . 2808126 . free .
  31. Chen LS, Redkar S, Taverna P, Cortes JE, Gandhi V . Mechanisms of cytotoxicity to Pim kinase inhibitor, SGI-1776, in acute myeloid leukemia . Blood . 118 . 3 . 693–702 . July 2011 . 21628411 . 10.1182/blood-2010-12-323022 . 3142906 . free .
  32. Foulks JM, Carpenter KJ, Luo B, Xu Y, Senina A, Nix R, Chan A, Clifford A, Wilkes M, Vollmer D, Brenning B, Merx S, Lai S, McCullar MV, Ho KK, Albertson DJ, Call LT, Bearss JJ, Tripp S, Liu T, Stephens BJ, Mollard A, Warner SL, Bearss DJ, Kanner SB . A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas . Neoplasia . 16 . 5 . 403–12 . May 2014 . 24953177 . 10.1016/j.neo.2014.05.004 . 4198696 . free .

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