PIM1

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Species	Human	Mouse
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Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the PIM1 gene.

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. Subsequently, the oncogene has been implicated in multiple human cancers, including prostate cancer, acute myeloid leukemia and other hematopoietic malignancies. 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. Pim-1 is mainly involved in cell cycle progression, apoptosis and transcriptional activation, as well as more general signal transduction pathways.

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. 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. In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar. The Pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD.

Protein structure

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

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. 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. Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1.

Interactions

PIM1 has been shown to interact with:

• CBX3,
• CDC25A,
• Heat shock protein 90kDa alpha (cytosolic), member A1,
• NFATC1,
• Nuclear mitotic apparatus protein 1,
• P21,
• SND1 and
• RELA.

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). 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.

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
• Cdc25C (G₂/M positive regulator): Activation results in increased G₂ → M

Deactivates

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

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. 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. PIM expression is sufficient to drive resistance to anti-angiogenic agents in prostate and colon cancer models, although the mechanism is not fully elucidated.

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.

Examples

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

Further reading

• Ragoussis J, Senger G, Mockridge I, Sanseau P, Ruddy S, Dudley K, Sheer D, Trowsdale J (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. PMID 1427894.
• Saris CJ, Domen J, Berns A (March 1991). "The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG". The EMBO Journal. 10 (3): 655–64. PMC 452698. PMID 1825810.
• Reeves R, Spies GA, Kiefer M, Barr PJ, Power M (June 1990). "Primary structure of the putative human oncogene, pim-1". Gene. 90 (2): 303–7. doi:10.1016/0378-1119(90)90195-W. PMID 2205533.
• Amson R, Sigaux F, Przedborski S, Flandrin G, Givol D, Telerman A (November 1989). "The human protooncogene product p33pim is expressed during fetal hematopoiesis and in diverse leukemias". Proceedings of the National Academy of Sciences of the United States of America. 86 (22): 8857–61. doi:10.1073/pnas.86.22.8857. PMC 298389. PMID 2682662.
• Telerman A, Amson R, Zakut-Houri R, Givol D (April 1988). "Identification of the human pim-1 gene product as a 33-kilodalton cytoplasmic protein with tyrosine kinase activity". Molecular and Cellular Biology. 8 (4): 1498–503. doi:10.1128/mcb.8.4.1498. PMC 363308. PMID 2837645.
• Meeker TC, Nagarajan L, ar-Rushdi A, Croce CM (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. PMID 3429489.
• Zakut-Houri R, Hazum S, Givol D, Telerman A (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. PMID 3475233.
• 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.
• 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.
• 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.
• Maita H, Harada Y, Nagakubo D, Kitaura H, Ikeda M, Tamai K, Takahashi K, Ariga H, Iguchi-Ariga SM (August 2000). "PAP-1, a novel target protein of phosphorylation by pim-1 kinase". European Journal of Biochemistry. 267 (16): 5168–78. doi:10.1046/j.1432-1327.2000.01585.x. PMID 10931201.
• 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.
• 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 (June 2001). "Sorting nexin 6, a novel SNX, interacts with the transforming growth factor-beta family of receptor serine-threonine kinases". The Journal of Biological Chemistry. 276 (22): 19332–9. doi:10.1074/jbc.M100606200. PMID 11279102.
• Wang Z, Bhattacharya N, Meyer MK, Seimiya H, Tsuruo T, Tonani JA, Magnuson NS (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. PMID 11368509.
• Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, Küppers R, Dalla-Favera R (July 2001). "Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas". Nature. 412 (6844): 341–6. doi:10.1038/35085588. PMID 11460166.
• Ishibashi Y, Maita H, Yano M, Koike N, Tamai K, Ariga H, Iguchi-Ariga SM (September 2001). "Pim-1 translocates sorting nexin 6/TRAF4-associated factor 2 from cytoplasm to nucleus". FEBS Letters. 506 (1): 33–8. doi:10.1016/S0014-5793(01)02881-2. PMID 11591366.
• 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.
• Nieborowska-Skorska M, Hoser G, Kossev P, Wasik MA, Skorski T (June 2002). "Complementary functions of the antiapoptotic protein A1 and serine/threonine kinase pim-1 in the BCR/ABL-mediated leukemogenesis". Blood. 99 (12): 4531–9. doi:10.1182/blood.V99.12.4531. PMID 12036885.
• 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.