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词条 PIM1
释义

  1. Gene

  2. Protein structure

  3. Activation and stabilization

  4. Interactions

      Activates    Deactivates  

  5. Clinical implications

  6. Inhibitors

  7. References

  8. Further reading

{{Infobox_gene}}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:

  • CBX3,[6]
  • CDC25A,[7]
  • Heat shock protein 90kDa alpha (cytosolic), member A1,[8]
  • NFATC1,[9]
  • Nuclear mitotic apparatus protein 1,[10]
  • P21,[11]
  • SND1[12] and
  • RELA.[13]

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
  • AZD1208
  • LGH447
  • SGI-1776
  • TP-3654

References

1. ^{{cite web | title = Entrez Gene: PIM1 pim-1 oncogene| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5292| accessdate = }}
2. ^{{cite journal | vauthors = Domen J, Von Lindern M, Hermans A, Breuer M, Grosveld G, Berns A | title = Comparison of the human and mouse PIM-1 cDNAs: nucleotide sequence and immunological identification of the in vitro synthesized PIM-1 protein | journal = Oncogene Research | volume = 1 | issue = 1 | pages = 103–12 | date = June 1987 | pmid = 3329709 | doi = }}
3. ^{{cite journal | vauthors = Meeker TC, Nagarajan L, ar-Rushdi A, Rovera G, Huebner K, Croce CM | title = Characterization of the human PIM-1 gene: a putative proto-oncogene coding for a tissue specific member of the protein kinase family | journal = Oncogene Research | volume = 1 | issue = 1 | pages = 87–101 | date = June 1987 | pmid = 3329711 | doi = }}
4. ^1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 {{cite journal | vauthors = Bachmann M, Möröy T | title = The serine/threonine kinase Pim-1 | journal = The International Journal of Biochemistry & Cell Biology | volume = 37 | issue = 4 | pages = 726–30 | date = April 2005 | pmid = 15694833 | doi = 10.1016/j.biocel.2004.11.005 }}
5. ^{{cite web | title = Pim-1 Oncogene| url = http://atlasgeneticsoncology.org/Genes/GC_PIM1.html| accessdate = 2015-12-14 }}
6. ^{{cite journal | vauthors = Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM | title = 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) | journal = FEBS Letters | volume = 467 | issue = 1 | pages = 17–21 | date = February 2000 | pmid = 10664448 | doi = 10.1016/S0014-5793(00)01105-4 }}
7. ^{{cite journal | vauthors = Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y | title = Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway | journal = The Journal of Biological Chemistry | volume = 274 | issue = 26 | pages = 18659–66 | date = June 1999 | pmid = 10373478 | doi = 10.1074/jbc.274.26.18659 }}
8. ^{{cite journal | vauthors = Mizuno K, Shirogane T, Shinohara A, Iwamatsu A, Hibi M, Hirano T | title = Regulation of Pim-1 by Hsp90 | journal = Biochemical and Biophysical Research Communications | volume = 281 | issue = 3 | pages = 663–9 | date = March 2001 | pmid = 11237709 | doi = 10.1006/bbrc.2001.4405 }}
9. ^{{cite journal | vauthors = Rainio EM, Sandholm J, Koskinen PJ | title = Cutting edge: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase | journal = Journal of Immunology | volume = 168 | issue = 4 | pages = 1524–7 | date = February 2002 | pmid = 11823475 | doi = 10.4049/jimmunol.168.4.1524 }}
10. ^{{cite journal | vauthors = Bhattacharya N, Wang Z, Davitt C, McKenzie IF, Xing PX, Magnuson NS | title = Pim-1 associates with protein complexes necessary for mitosis | journal = Chromosoma | volume = 111 | issue = 2 | pages = 80–95 | date = July 2002 | pmid = 12111331 | doi = 10.1007/s00412-002-0192-6 }}
11. ^{{cite journal | vauthors = Wang Z, Bhattacharya N, Mixter PF, Wei W, Sedivy J, Magnuson NS | title = Phosphorylation of the cell cycle inhibitor p21Cip1/WAF1 by Pim-1 kinase | journal = Biochimica et Biophysica Acta | volume = 1593 | issue = 1 | pages = 45–55 | date = December 2002 | pmid = 12431783 | doi = 10.1016/S0167-4889(02)00347-6 }}
12. ^{{cite journal | vauthors = Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen KJ, Dash AB, Eisenman RN, Ness SA | title = Pim-1 kinase and p100 cooperate to enhance c-Myb activity | journal = Molecular Cell | volume = 2 | issue = 4 | pages = 417–25 | date = October 1998 | pmid = 9809063 | doi = 10.1016/S1097-2765(00)80141-0 }}
13. ^{{cite journal | vauthors = Nihira K, Ando Y, Yamaguchi T, Kagami Y, Miki Y, Yoshida K | title = Pim-1 controls NF-kappaB signalling by stabilizing RelA/p65 | journal = Cell Death and Differentiation | volume = 17 | issue = 4 | pages = 689–98 | date = April 2010 | pmid = 19911008 | doi = 10.1038/cdd.2009.174 }}
14. ^{{cite journal | vauthors = Wang J, Kim J, Roh M, Franco OE, Hayward SW, Wills ML, Abdulkadir SA | title = Pim1 kinase synergizes with c-MYC to induce advanced prostate carcinoma | journal = Oncogene | volume = 29 | issue = 17 | pages = 2477–87 | date = April 2010 | pmid = 20140016 | pmc = 2861731 | doi = 10.1038/onc.2010.10 }}
15. ^{{cite journal | vauthors = Kim DS, Sung JS, Shin ES, Ryu JS, Choi IK, Park KH, Park Y, Kim EB, Park SJ, Kim YH | title = Association of single nucleotide polymorphisms in PIM-1 gene with the risk of Korean lung cancer | journal = Cancer Research and Treatment | volume = 40 | issue = 4 | pages = 190–6 | date = December 2008 | pmid = 19688129 | pmc = 2697471 | doi = 10.4143/crt.2008.40.4.190 }}
16. ^{{cite journal | vauthors = Velazquez R, Shaw DM, Caccamo A, Oddo S | title = Pim1 inhibition as a novel therapeutic strategy for Alzheimer's disease | journal = Molecular Neurodegeneration | volume = 11 | issue = 1 | pages = 52 | date = July 2016 | pmid = 27412291 | doi = 10.1186/s13024-016-0118-z | pmc=4944476}}
17. ^{{cite journal | vauthors = Casillas AL, Toth RK, Sainz AG, Singh N, Desai AA, Kraft AS, Warfel NA | title = Hypoxia-Inducible PIM Kinase Expression Promotes Resistance to Antiangiogenic Agents | journal = Clinical Cancer Research | volume = 24 | issue = 1 | pages = 169–180 | year = 2018 | pmid = 29084916 | doi = 10.1158/1078-0432.CCR-17-1318 }}
18. ^{{cite journal | vauthors = Morwick T | title = Pim kinase inhibitors: a survey of the patent literature | journal = Expert Opinion on Therapeutic Patents | volume = 20 | issue = 2 | pages = 193–212 | date = February 2010 | pmid = 20100002 | doi = 10.1517/13543770903496442 }}
19. ^{{cite journal | vauthors = Merkel AL, Meggers E, Ocker M | title = PIM1 kinase as a target for cancer therapy | journal = Expert Opinion on Investigational Drugs | volume = 21 | issue = 4 | pages = 425–36 | date = April 2012 | pmid = 22385334 | doi = 10.1517/13543784.2012.668527 }}
20. ^{{cite journal | vauthors = 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 | title = A small-molecule inhibitor of PIM kinases as a potential treatment for urothelial carcinomas | journal = Neoplasia | volume = 16 | issue = 5 | pages = 40312 | date = May 2014 | pmid = 24953177 | doi = 10.1016/j.neo.2014.05.004 | pmc=4198696}}
21. ^{{cite journal | vauthors = Arunesh GM, Shanthi E, Krishna MH, Sooriya Kumar J, Viswanadhan VN | title = Small molecule inhibitors of PIM1 kinase: July 2009 to February 2013 patent update | journal = Expert Opinion on Therapeutic Patents | volume = 24 | issue = 1 | pages = 5–17 | date = January 2014 | pmid = 24131033 | doi = 10.1517/13543776.2014.848196 }}
22. ^{{cite journal | vauthors = Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M | title = Targeting the Pim kinases in multiple myeloma | journal = Blood Cancer Journal | volume = 5 | pages = e325 | date = July 2015 | pmid = 26186558 | doi = 10.1038/bcj.2015.46 | pmc=4526774}}
23. ^{{cite journal | vauthors = Le BT, Kumarasiri M, Adams JR, Yu M, Milne R, Sykes MJ, Wang S | title = Targeting Pim kinases for cancer treatment: opportunities and challenges | journal = Future Medicinal Chemistry | volume = 7 | issue = 1 | pages = 35–53 | date = 2015 | pmid = 25582332 | doi = 10.4155/fmc.14.145 }}
24. ^{{cite journal | vauthors = Tursynbay Y, Zhang J, Li Z, Tokay T, Zhumadilov Z, Wu D, Xie Y | title = Pim-1 kinase as cancer drug target: An update | journal = Biomedical Reports | volume = 4 | issue = 2 | pages = 140–146 | date = February 2016 | pmid = 26893828 | doi = 10.3892/br.2015.561 | pmc=4734217}}

Further reading

{{Refbegin | 2}}
  • {{cite journal | vauthors = Ragoussis J, Senger G, Mockridge I, Sanseau P, Ruddy S, Dudley K, Sheer D, Trowsdale J | title = 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 | journal = Genomics | volume = 14 | issue = 3 | pages = 673–9 | date = November 1992 | pmid = 1427894 | doi = 10.1016/S0888-7543(05)80167-3 }}
  • {{cite journal | vauthors = Saris CJ, Domen J, Berns A | title = The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG | journal = The EMBO Journal | volume = 10 | issue = 3 | pages = 655–64 | date = March 1991 | pmid = 1825810 | pmc = 452698 | doi = }}
  • {{cite journal | vauthors = Reeves R, Spies GA, Kiefer M, Barr PJ, Power M | title = Primary structure of the putative human oncogene, pim-1 | journal = Gene | volume = 90 | issue = 2 | pages = 303–7 | date = June 1990 | pmid = 2205533 | doi = 10.1016/0378-1119(90)90195-W }}
  • {{cite journal | vauthors = Amson R, Sigaux F, Przedborski S, Flandrin G, Givol D, Telerman A | title = The human protooncogene product p33pim is expressed during fetal hematopoiesis and in diverse leukemias | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 86 | issue = 22 | pages = 8857–61 | date = November 1989 | pmid = 2682662 | pmc = 298389 | doi = 10.1073/pnas.86.22.8857 }}
  • {{cite journal | vauthors = Telerman A, Amson R, Zakut-Houri R, Givol D | title = Identification of the human pim-1 gene product as a 33-kilodalton cytoplasmic protein with tyrosine kinase activity | journal = Molecular and Cellular Biology | volume = 8 | issue = 4 | pages = 1498–503 | date = April 1988 | pmid = 2837645 | pmc = 363308 | doi = 10.1128/mcb.8.4.1498}}
  • {{cite journal | vauthors = Meeker TC, Nagarajan L, ar-Rushdi A, Croce CM | title = Cloning and characterization of the human PIM-1 gene: a putative oncogene related to the protein kinases | journal = Journal of Cellular Biochemistry | volume = 35 | issue = 2 | pages = 105–12 | date = October 1987 | pmid = 3429489 | doi = 10.1002/jcb.240350204 }}
  • {{cite journal | vauthors = Zakut-Houri R, Hazum S, Givol D, Telerman A | title = The cDNA sequence and gene analysis of the human pim oncogene | journal = Gene | volume = 54 | issue = 1 | pages = 105–11 | year = 1987 | pmid = 3475233 | doi = 10.1016/0378-1119(87)90352-0 }}
  • {{cite journal | vauthors = Leverson JD, Koskinen PJ, Orrico FC, Rainio EM, Jalkanen KJ, Dash AB, Eisenman RN, Ness SA | title = Pim-1 kinase and p100 cooperate to enhance c-Myb activity | journal = Molecular Cell | volume = 2 | issue = 4 | pages = 417–25 | date = October 1998 | pmid = 9809063 | doi = 10.1016/S1097-2765(00)80141-0 }}
  • {{cite journal | vauthors = Mochizuki T, Kitanaka C, Noguchi K, Muramatsu T, Asai A, Kuchino Y | title = Physical and functional interactions between Pim-1 kinase and Cdc25A phosphatase. Implications for the Pim-1-mediated activation of the c-Myc signaling pathway | journal = The Journal of Biological Chemistry | volume = 274 | issue = 26 | pages = 18659–66 | date = June 1999 | pmid = 10373478 | doi = 10.1074/jbc.274.26.18659 }}
  • {{cite journal | vauthors = Koike N, Maita H, Taira T, Ariga H, Iguchi-Ariga SM | title = 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) | journal = FEBS Letters | volume = 467 | issue = 1 | pages = 17–21 | date = February 2000 | pmid = 10664448 | doi = 10.1016/S0014-5793(00)01105-4 }}
  • {{cite journal | vauthors = Maita H, Harada Y, Nagakubo D, Kitaura H, Ikeda M, Tamai K, Takahashi K, Ariga H, Iguchi-Ariga SM | title = PAP-1, a novel target protein of phosphorylation by pim-1 kinase | journal = European Journal of Biochemistry | volume = 267 | issue = 16 | pages = 5168–78 | date = August 2000 | pmid = 10931201 | doi = 10.1046/j.1432-1327.2000.01585.x }}
  • {{cite journal | vauthors = Mizuno K, Shirogane T, Shinohara A, Iwamatsu A, Hibi M, Hirano T | title = Regulation of Pim-1 by Hsp90 | journal = Biochemical and Biophysical Research Communications | volume = 281 | issue = 3 | pages = 663–9 | date = March 2001 | pmid = 11237709 | doi = 10.1006/bbrc.2001.4405 }}
  • {{cite journal | vauthors = Parks WT, Frank DB, Huff C, Renfrew Haft C, Martin J, Meng X, de Caestecker MP, McNally JG, Reddi A, Taylor SI, Roberts AB, Wang T, Lechleider RJ | title = Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases | journal = The Journal of Biological Chemistry | volume = 276 | issue = 22 | pages = 19332–9 | date = June 2001 | pmid = 11279102 | doi = 10.1074/jbc.M100606200 }}
  • {{cite journal | vauthors = Wang Z, Bhattacharya N, Meyer MK, Seimiya H, Tsuruo T, Tonani JA, Magnuson NS | title = Pim-1 negatively regulates the activity of PTP-U2S phosphatase and influences terminal differentiation and apoptosis of monoblastoid leukemia cells | journal = Archives of Biochemistry and Biophysics | volume = 390 | issue = 1 | pages = 9–18 | date = June 2001 | pmid = 11368509 | doi = 10.1006/abbi.2001.2370 }}
  • {{cite journal | vauthors = Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Küppers R, Dalla-Favera R | title = Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas | journal = Nature | volume = 412 | issue = 6844 | pages = 341–6 | date = July 2001 | pmid = 11460166 | doi = 10.1038/35085588 }}
  • {{cite journal | vauthors = Ishibashi Y, Maita H, Yano M, Koike N, Tamai K, Ariga H, Iguchi-Ariga SM | title = Pim-1 translocates sorting nexin 6/TRAF4-associated factor 2 from cytoplasm to nucleus | journal = FEBS Letters | volume = 506 | issue = 1 | pages = 33–8 | date = September 2001 | pmid = 11591366 | doi = 10.1016/S0014-5793(01)02881-2 }}
  • {{cite journal | vauthors = Rainio EM, Sandholm J, Koskinen PJ | title = Cutting edge: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase | journal = Journal of Immunology | volume = 168 | issue = 4 | pages = 1524–7 | date = February 2002 | pmid = 11823475 | doi = 10.4049/jimmunol.168.4.1524 }}
  • {{cite journal | vauthors = Nieborowska-Skorska M, Hoser G, Kossev P, Wasik MA, Skorski T | title = Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis | journal = Blood | volume = 99 | issue = 12 | pages = 4531–9 | date = June 2002 | pmid = 12036885 | doi = 10.1182/blood.V99.12.4531 }}
  • {{cite journal | vauthors = Bhattacharya N, Wang Z, Davitt C, McKenzie IF, Xing PX, Magnuson NS | title = Pim-1 associates with protein complexes necessary for mitosis | journal = Chromosoma | volume = 111 | issue = 2 | pages = 80–95 | date = July 2002 | pmid = 12111331 | doi = 10.1007/s00412-002-0192-6 }}
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