Alternative titles; symbols
HGNC Approved Gene Symbol: PIM1
Cytogenetic location: 6p21.2 Genomic coordinates (GRCh38): 6:37,170,152-37,175,428 (from NCBI)
The protooncogene PIM1 encodes a protein kinase upregulated in prostate cancer (Dhanasekaran et al., 2001).
Viral leukemogenesis in mice is often initiated by proviral activation of the highly conserved cellular gene Pim1. Domen et al. (1987) compared the nucleotide sequence of human and mouse PIM1 cDNAs. Meeker et al. (1987) also characterized the human PIM1 gene. The deduced amino acid sequence showed significant homology to a number of the protein kinases but did not have a transmembrane region. Studies of expression of this gene using Northern blots of human cell lines showed it to be transcribed primarily in B-lymphoid and myeloid cell lines.
Amson et al. (1989) showed that the 33-kD product of the PIM gene is highly expressed in the liver and spleen during fetal hematopoiesis. In contrast, it is only slightly expressed in circulating granulocytes in adults. It was overexpressed in hematopoietic malignancies, particularly in myeloid and lymphoid acute leukemias. The results implied a physiologic role of the PIM1 oncogene during hematopoietic development and a deregulation of the gene in various leukemias.
Saris et al. (1991) provided evidence that both the murine and the human PIM1 gene products are protein-serine/threonine kinases. In the mouse, at any rate, they showed that the gene encodes both a 44- and a 34-kD protein, the former being an amino-terminal extension of the latter which is synthesized by alternative translation initiation at an upstream CUG codon.
Using cDNA microarrays, Dhanasekaran et al. (2001) examined gene expression profiles of more than 50 normal and neoplastic prostate specimens and 3 common prostate cancer cell lines. Signature expression profiles of normal adjacent prostate, benign prostatic hypertrophy, localized prostate cancer, and metastatic, hormone-refractory prostate cancer were determined. Dhanasekaran et al. (2001) established many associations between genes and prostate cancer. They assessed 2 of these genes, hepsin (142440), a transmembrane serine protease, and PIM1, a serine/threonine kinase, at the protein level using tissue microarrays consisting of over 700 clinically stratified prostate cancer specimens. Expression of hepsin and PIM1 proteins was significantly correlated with measures of clinical outcome.
Using immunofluorescence analysis, Muraski et al. (2007) found that PIM1 showed cytoplasmic expression in normal adult human myocardium, but it adopted a predominantly nuclear localization in failing human hearts. PIM1 mRNA and protein abundance were also increased in failing myocardium compared with normal controls. In a mouse model, perinuclear Pim1 immunoreactivity increased in border-zone cardiomyocytes after pressure overload-induced myocardial infarction. Cardioprotective stimuli associated with Akt (164730) activation induced Pim1 expression, and cardioprotection was not observed in Pim1-deficient mice. Transgenic expression of Pim1 in myocardium protected mice from infarction injury by activation of antiapoptotic signaling, with concomitant increases in Bcl2 (151430) and Bclxl (600039) protein levels and Bad (603167) phosphorylation. Calcium dynamics were significantly enhanced in Pim1-overexpressing transgenic hearts in association with increased Serca2a (ATP2A2; 108740) expression, and they were depressed in Pim1-deficient hearts. Muraski et al. (2007) concluded that PIM1 has a role in cardioprotection downstream of AKT activation.
Meeker et al. (1987) analyzed genomic PIM1 clones from a human B cell leukemia line. The PIM1 transcript was found to derive from 5 kb of genomic DNA. Six exons and 5 introns were identified.
By means of Southern blot analysis of DNA from somatic cell hybrids, Cuypers et al. (1986) assigned the human homolog of the murine PIM1 oncogene to 6pter-q12. In the mouse, this gene is located on chromosome 17. By a combination of deletion and linkage mapping, Zoghbi et al. (1990) determined that the PIM1 locus is located between the MUT locus (609058) and the HLA cluster, i.e., between 6p21.3 and 6p12. They identified RFLPs at the PIM1 locus. By fluorescence in situ hybridization, Ragoussis et al. (1992) refined the assignment to 6p21.2. Ark et al. (1991) provided refined mapping of the Pim1 locus in the mouse and used the Pim1 gene as a marker for further genetic analysis of t-haplotypes on mouse chromosome 17.
In addition to immunoglobulin V genes, the 5-prime sequences of BCL6 (109565) and FAS (TNFRSF6; 134637) are mutated in normal germinal center B lymphocytes. Genomic instability promotes tumorigenesis through defective chromosome segregation and DNA mismatch repair inactivation. By screening 18 loci for mutations, Pasqualucci et al. (2001) identified changes in the germline sequences of PIM1, MYC (190080), ARHH (602037), and/or PAX5 (167414), in addition to BCL6, in a majority of diffuse large-cell lymphomas (DLCLs; see 601889). No mutations in PIM1, MYC, ARHH, and PAX5 were detected in germinal-center lymphocytes, naive B cells, or B-cell malignancies other than DLCLs. Most PIM1 mutations, which were found in 43% of DLCLs, were located in a 1.2-kb stretch of the first 2 kb from the transcription initiation site and were predicted to alter the structure and, in some cases, the function of PIM1. FISH analysis indicated that hypermutation in these genes is not due to chromosomal translocation, as seen in Burkitt lymphoma (113970). Chromosomal translocation, however, may be an outcome of hypermutation. Specific features of the hypermutation process, including the predominance of single nucleotide substitutions with occasional deletions or duplications, a preference for transitions over transversions, and a specific motif targeting RGYW, were recognizable in each of the hypermutated loci. Pasqualucci et al. (2001) proposed that aberrant hypermutation of regulatory and coding sequences of genes that do not represent physiologic targets may provide the basis for DLCL pathogenesis and explain its phenotypic and clinical heterogeneity. This hypermutation malfunction is unlikely to be due to defective DNA mismatch repair and does not appear to involve activation-induced deaminase (AICDA; 605257)
To understand the function of Pim1 and its role in hematopoietic development, Laird et al. (1993) generated mice deficient in Pim1 function. Pim1-deficient mice were ostensibly normal, healthy, and fertile; however, detailed analysis demonstrated a correlation of Pim1 deficiency with erythrocyte microcytosis, whereas overexpression of Pim1 in transgenic mice resulted in erythrocyte macrocytosis.
Mikkers et al. (2004) generated compound Pim-deficient mice lacking Pim1, Pim2 (300295), and Pim3 (610580). These mice were viable and fertile, but their body size was reduced at birth and throughout postnatal life. Proliferation of hematopoietic cells in response to growth factors was impaired in vitro and in vivo. In addition, Pim proteins were required for efficient cell cycle induction of peripheral T cells in response to synergistic T-cell receptor (see 186790) and interleukin-2 (IL2; 147680) signaling.
Amson, R., Sigaux, F., Przedborski, S., Flandrin, G., Givol, D., Telerman, A. The human protooncogene product p33pim is expressed during fetal hematopoiesis and in diverse leukemias. Proc. Nat. Acad. Sci. 86: 8857-8861, 1989. [PubMed: 2682662] [Full Text: https://doi.org/10.1073/pnas.86.22.8857]
Ark, B., Gummere, G., Bennett, D., Artzt, K. Mapping of the Pim-1 oncogene in mouse t-haplotypes and its use to define the relative map positions of the tcl loci t-0(t-6) and t-w12 and the marker tf (tufted). Genomics 10: 385-389, 1991. [PubMed: 1676981] [Full Text: https://doi.org/10.1016/0888-7543(91)90323-7]
Cuypers, H. T., Selten, G., Berns, A., Geurts van Kessel, A. H. M. Assignment of the human homologue of Pim-1, a mouse gene implicated in leukemogenesis, to the pter-q12 region of chromosome 6. Hum. Genet. 72: 262-265, 1986. [PubMed: 3754237] [Full Text: https://doi.org/10.1007/BF00291892]
Dhanasekaran, S. M., Barrette, T. R., Ghosh, D., Shah, R., Varambally, S., Kurachi, K., Pienta, K. J., Rubin, M. A., Chinnaiyan, A. M. Delineation of prognostic biomarkers in prostate cancer. Nature 412: 822-826, 2001. [PubMed: 11518967] [Full Text: https://doi.org/10.1038/35090585]
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 Res. 1: 103-112, 1987. [PubMed: 3329709]
Laird, P. W., van der Lugt, N. M. T., Clarke, A., Domen, J., Linders, K., McWhir, J., Berns, A., Hooper, M. In vivo analysis of Pim-1 deficiency. Nucleic Acids Res. 21: 4750-4755, 1993. Note: Erratum: Nucleic Acids Res. 51: 10107, 2023. [PubMed: 8233823] [Full Text: https://doi.org/10.1093/nar/21.20.4750]
Meeker, T. C., Nagarajan, L., ar-Rushdi, A., Rovera, G., Huebner, K., Croce, C. M. Characterization of the human PIM-1 gene: a putative proto-oncogene coding for a tissue specific member of the protein kinase family. Oncogene Res. 1: 87-101, 1987. [PubMed: 3329711]
Mikkers, H., Nawijn, M., Allen, J., Brouwers, C., Verhoeven, E., Jonkers, J., Berns, A. Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Molec. Cell. Biol. 24: 6104-6115, 2004. [PubMed: 15199164] [Full Text: https://doi.org/10.1128/MCB.24.13.6104-6115.2004]
Muraski, J. A., Rota, M., Misao, Y., Fransioli, J., Cottage, C., Gude, N., Esposito, G., Delucchi, F., Arcarese, M., Alvarez, R., Siddiqi, S., Emmanuel, G. N., and 13 others. Pim-1 regulates cardiomyocyte survival downstream of Akt. Nature Med. 13: 1467-1475, 2007. Note: Erratum: Nature Med. 14: 350 only, 2008. [PubMed: 18037896] [Full Text: https://doi.org/10.1038/nm1671]
Pasqualucci, L., Neumeister, P., Goossens, T., Nanjangud, G., Chaganti, R. S. K., Kuppers, R., Dalla-Favera, R. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412: 341-346, 2001. [PubMed: 11460166] [Full Text: https://doi.org/10.1038/35085588]
Ragoussis, J., Senger, G., Mockridge, I., Sanseau, P., Ruddy, S., Dudley, K., Sheer, D., Trowsdale, J. 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: 673-679, 1992. [PubMed: 1427894] [Full Text: https://doi.org/10.1016/s0888-7543(05)80167-3]
Saris, C. J. M., Domen, J., Berns, A. The pim-1 oncogene encodes two related protein-serine/threonine kinases by alternative initiation at AUG and CUG. EMBO J. 10: 655-664, 1991. [PubMed: 1825810] [Full Text: https://doi.org/10.1002/j.1460-2075.1991.tb07994.x]
Selten, G., Cuypers, H. T., Boelens, W., Robanus-Maandag, E., Verbeek, J., Domen, J., van Beveren, C., Berns, A. The primary structure of the putative oncogene pim-1 shows extensive homology with protein kinases. Cell 46: 603-611, 1986. [PubMed: 3015420] [Full Text: https://doi.org/10.1016/0092-8674(86)90886-x]
Zoghbi, H. Y., Ballantyne, C. M., O'Brien, W. E., McCall, A. E., Kwiatkowski, T. J., Jr., Ledbetter, S. A., Beaudet, A. L. Deletion and linkage mapping of eight markers from the proximal short arm of chromosome 6. Genomics 6: 352-357, 1990. [PubMed: 1968423] [Full Text: https://doi.org/10.1016/0888-7543(90)90576-g]