PIM1

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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]

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.[14]

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

Activates

  • Cdc25C (G1/S positive regulator): Activation results in increased G1 → S[4]
  • Cdc25C (G2/M positive regulator): Activation results in increased G2 → M[4]

Deactivates

  • Bad (Pro-apoptotic protein): Deactivation results in increased cell survival[4]
  • CKI (G1/S negative regulator): Deactivation results in increased G1 → S[4]
  • C-TAK1 (Cdc25C inhibitor): Deactivation results in increased G2 → M[4]

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.[15] As well as showing useful activity against a range of cancers, PIM kinase inhibitors have also been suggested as possible treatments for Alzheimer's disease.[16] PIM expression is sufficient to drive resistance to anti-angiogenic agents in prostate and colon cancer models, although the mechanism is not fully elucidated.[17]

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.[18][19][20][21][22][23][24]

Examples

References

  1. ↑ "Entrez Gene: PIM1 pim-1 oncogene".
  2. ↑ Domen J, Von Lindern M, Hermans A, Breuer M, Grosveld G, Berns A (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. PMID 3329709.
  3. ↑ Meeker TC, Nagarajan L, ar-Rushdi A, Rovera G, Huebner K, Croce CM (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. PMID 3329711.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 4.17 Bachmann M, Möröy T (April 2005). "The serine/threonine kinase Pim-1". The International Journal of Biochemistry & Cell Biology. 37 (4): 726–30. doi:10.1016/j.biocel.2004.11.005. PMID 15694833.
  5. ↑ "Pim-1 Oncogene". Retrieved 2015-12-14.
  6. ↑ Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM (February 2000). "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. doi:10.1016/S0014-5793(00)01105-4. PMID 10664448.
  7. ↑ Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y (June 1999). "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. doi:10.1074/jbc.274.26.18659. PMID 10373478.
  8. ↑ Mizuno K, Shirogane T, Shinohara A, Iwamatsu A, Hibi M, Hirano T (March 2001). "Regulation of Pim-1 by Hsp90". Biochemical and Biophysical Research Communications. 281 (3): 663–9. doi:10.1006/bbrc.2001.4405. PMID 11237709.
  9. ↑ Rainio EM, Sandholm J, Koskinen PJ (February 2002). "Cutting edge: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase". Journal of Immunology. 168 (4): 1524–7. doi:10.4049/jimmunol.168.4.1524. PMID 11823475.
  10. ↑ Bhattacharya N, Wang Z, Davitt C, McKenzie IF, Xing PX, Magnuson NS (July 2002). "Pim-1 associates with protein complexes necessary for mitosis". Chromosoma. 111 (2): 80–95. doi:10.1007/s00412-002-0192-6. PMID 12111331.
  11. ↑ Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS (December 2002). "Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase". Biochimica et Biophysica Acta. 1593 (1): 45–55. doi:10.1016/S0167-4889(02)00347-6. PMID 12431783.
  12. ↑ Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen KJ, Dash AB, Eisenman RN, Ness SA (October 1998). "Pim-1 kinase and p100 cooperate to enhance c-Myb activity". Molecular Cell. 2 (4): 417–25. doi:10.1016/S1097-2765(00)80141-0. PMID 9809063.
  13. ↑ Nihira K, Ando Y, Yamaguchi T, Kagami Y, Miki Y, Yoshida K (April 2010). "Pim-1 controls NF-kappaB signalling by stabilizing RelA/p65". Cell Death and Differentiation. 17 (4): 689–98. doi:10.1038/cdd.2009.174. PMID 19911008.
  14. ↑ Wang J, Kim J, Roh M, Franco OE, Hayward SW, Wills ML, Abdulkadir SA (April 2010). "Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma". Oncogene. 29 (17): 2477–87. doi:10.1038/onc.2010.10. PMC 2861731. PMID 20140016.
  15. ↑ Kim DS, Sung JS, Shin ES, Ryu JS, Choi IK, Park KH, Park Y, Kim EB, Park SJ, Kim YH (December 2008). "Association of single nucleotide polymorphisms in PIM-1 gene with the risk of Korean lung cancer". Cancer Research and Treatment. 40 (4): 190–6. doi:10.4143/crt.2008.40.4.190. PMC 2697471. PMID 19688129.
  16. ↑ Velazquez R, Shaw DM, Caccamo A, Oddo S (July 2016). "Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease". Molecular Neurodegeneration. 11 (1): 52. doi:10.1186/s13024-016-0118-z. PMC 4944476. PMID 27412291.
  17. ↑ Casillas AL, Toth RK, Sainz AG, Singh N, Desai AA, Kraft AS, Warfel NA (2018). "Hypoxia-Inducible PIM Kinase Expression Promotes Resistance to Antiangiogenic Agents". Clinical Cancer Research. 24 (1): 169–180. doi:10.1158/1078-0432.CCR-17-1318. PMID 29084916.
  18. ↑ Morwick T (February 2010). "Pim kinase inhibitors: a survey of the patent literature". Expert Opinion on Therapeutic Patents. 20 (2): 193–212. doi:10.1517/13543770903496442. PMID 20100002.
  19. ↑ Merkel AL, Meggers E, Ocker M (April 2012). "PIM1 kinase as a target for cancer therapy". Expert Opinion on Investigational Drugs. 21 (4): 425–36. doi:10.1517/13543784.2012.668527. PMID 22385334.
  20. ↑ 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 (May 2014). "A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas". Neoplasia. 16 (5): 40312. doi:10.1016/j.neo.2014.05.004. PMC 4198696. PMID 24953177.
  21. ↑ Arunesh GM, Shanthi E, Krishna MH, Sooriya Kumar J, Viswanadhan VN (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. PMID 24131033.
  22. ↑ Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M (July 2015). "Targeting the Pim kinases in multiple myeloma". Blood Cancer Journal. 5: e325. doi:10.1038/bcj.2015.46. PMC 4526774. PMID 26186558.
  23. ↑ Le BT, Kumarasiri M, Adams JR, Yu M, Milne R, Sykes MJ, Wang S (2015). "Targeting Pim kinases for cancer treatment: opportunities and challenges". Future Medicinal Chemistry. 7 (1): 35–53. doi:10.4155/fmc.14.145. PMID 25582332.
  24. ↑ Tursynbay Y, Zhang J, Li Z, Tokay T, Zhumadilov Z, Wu D, Xie Y (February 2016). "Pim-1 kinase as cancer drug target: An update". Biomedical Reports. 4 (2): 140–146. doi:10.3892/br.2015.561. PMC 4734217. PMID 26893828.

Further reading

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