Disease relevance of Pim1

• Pim1 cooperates with E2a-Pbx1 to facilitate the progression of thymic lymphomas in transgenic mice [1].
• We found retroviral integrations in c-myc and Pim1 as already reported but we also identified for the first time Notch1 as a RadLV common integration site [2].
• Pim-1 is an oncogene activated in mouse T-cell lymphomas induced by Moloney and AKR mink cell focus (MCF) viruses [3].
• To identify the mechanism by which the Pim kinases may affect the growth of prostate tumors, we expressed Pim-1, Pim-2, or a kinase-dead Pim-2 protein in human PC3 prostate cancer cells [4].
• Similar to MoMuLV wild-type tumors, 50% of CD4(+)8(+) Rag-deficient tumors carry a provirus near the Pim1 protooncogene [5].

Psychiatry related information on Pim1

• Transgenic mice expressing the Pim-1 kinase are predisposed to develop T-cell lymphomas with a long latency period of about 7-9 months [6].

High impact information on Pim1

• Over 50% of the early T-cell lymphomas show integration in the Pim-1 region [7].
• One clone frequently revealed variations in the molecular structure of the corresponding region (Pim-1) in other lymphomas [7].
• All integrations occur in a region spanning less than 20 kb and are associated with the transcriptional activation of a distinct region within the Pim-1 domain [7].
• Expression of a kinase-defective Pim-1 mutant attenuated gp130-mediated cell proliferation [8].
• Thus, Pim-1 and p100 appear to be components of a novel signal transduction pathway affecting c-Myb activity, linking all three to the cytokine-regulated control of hematopoietic cell growth, differentiation, and apoptosis [9].

Chemical compound and disease context of Pim1

• Transgenic mice that overexpress Pim-1 (E mu-Pim-1) have a low incidence of spontaneous T-cell lymphomas and an increased susceptibility to Moloney murine leukemia virus and N-ethyl-N-nitrosourea-induced lymphomas [10].
• BACKGROUND: The Pim-1 33-kDa protein is a serine/threonine protein kinase that is capable of enhancing the rate of occurrence of c-Myc-induced lymphomas, and functions to block factor-withdrawal and genotoxic stress-induced apoptosis [11].
• Elevated expression of the serine/threonine kinase Pim-1 increases the incidence of lymphomas in Pim-1 transgenic mice and has also been found to occur in some human cancers [12].

Biological context of Pim1

• Overexpression of Pim1 can also overcome some of the proliferative defects caused by defective interleukin signaling supporting a role of Pim1 in cell proliferation [13].
• However, Pim1 DNA rearrangements were frequently sub-stoichiometric and not present at all sites of involvement in an otherwise monoclonal lymphoma indicating that Pim1 activation occurred late in the course of lymphomagenesis [1].
• The Pim-1 proto-oncogene is one of the most potent collaborators of the myc proto-oncogenes in inducing lymphomagenesis in mice [14].
• Primary hematopoietic cells from Pim-2- and Pim-1/Pim-2-deficient animals failed to accumulate and underwent apoptosis in the presence of rapamycin [15].
• The putative oncogene Pim-1 in the mouse: its linkage and variation among t haplotypes [16].

Anatomical context of Pim1

• Pim-1 was previously mapped to chromosome 17 by somatic cell hybrids, and subsequently to the region between the hemoglobin alpha-chain pseudogene 4 (Hba-4ps) and the alpha-crystalline gene (Crya-1) by Southern blot analysis of DNA obtained from panels of recombinant inbred strains [3].
• Cytokine-induced Pim-1 and Pim-2 promote the rapamycin-resistant survival of lymphocytes [17].
• In addition, we show here that cultured lymph node cells from E mu-Pim-1 lpr/lpr mice are rescued from rapid apoptosis that normally occurs in nontransgenic lpr cells in vitro [6].
• Expression of Pim-1 is widespread and ranges from the hematopoietic and lymphoid system to prostate, testis and oral epithelial cells [18].
• Pim-1 expression can be induced by several external stimuli in particular by a number of cytokines relevant in the immune system, which led to the labeling of Pim-1 as a "booster" for the immune response [18].

Associations of Pim1 with chemical compounds

• The protein encoded by the qpim cDNA can autophosphorylate itself and share substrates with murine Pim-1, suggesting functional redundancy to other Pim family serine/threonine kinases [19].
• On implantation of the transfectants in nude mice, the growth of the cells expressing Pim-1 or Pim-2 was significantly faster than the growth of the control cells transfected with the neomycin-resistant gene or the kinase-dead Pim-2 protein [4].
• The serine/threonine kinase Pim-1 [18].
• The association of PAP-1 with Pim-1 was also shown in vivo in transfected cells [20].
• Pim-1 expression in situ was consistent with the documented profile of progesterone activity in mouse mammary glands [21].

Physical interactions of Pim1

• This result was confirmed in cell culture, where full-length murine Runx1 and Runx3 both coprecipitated and colocalized with Pim-1 [22].

Enzymatic interactions of Pim1

• However, the Pim-1 kinase does not directly phosphorylate or bind to STAT5 [23].

Regulatory relationships of Pim1

• The Pim1 gene was targeted by retroviral insertions in 48% of accelerated lymphomas whereas less than 5% contained activated c-Myc and none contained activated Pim2 [1].
• Expression of a Pim-1 transgene accelerates lymphoproliferation and inhibits apoptosis in lpr/lpr mice [6].
• Analysis of the CD25(+)/CD44(-,lo) DN subpopulation from these animals revealed that Gfi-1 inhibits and Pim-1 promotes the development of larger beta-selected cycling cells ('L subset') from smaller resting cells ('E subset') within this subpopulation [24].
• In addition and in contrast to signaling in Mo7e and BM6 cell lines, in FDC2-ER cells SCF and Epo each were shown to rapidly activate Pim 1 gene expression [25].
• We then investigated the signaling pathways by which CD40 regulates Pim-1 expression and found that CD40 up-regulates Pim-1 primarily via the activation of NF-kappaB [26].

Other interactions of Pim1

• Proviral tagging in E mu-myc transgenic mice lacking the Pim-1 proto-oncogene leads to compensatory activation of Pim-2 [14].
• We have applied proviral tagging in compound mutant Emu-myc/Pim1-/-/Pim2-/- mice to identify genes that can complement for the loss of Pim1 and Pim2 and, therefore, are able to synergize with c-myc in lymphomagenesis [13].
• The inapt transcriptional regulation ability of the mutated Stat5b is proved by decreased levels of RNA of Stat5b-regulated genes (IL-2Rbeta and Pim1) [27].
• The deduced amino acid (aa) sequence of the cDNA, named qpim, is more closely related to Xenopus Pim and to the recently identified rat Pim-3 than to human or rodent Pim-1 or Pim-2 [19].
• Mapping of the Pim-1 oncogene in mouse t-haplotypes and its use to define the relative map positions of the tcl loci t0(t6) and tw12 and the marker tf (tufted) [3].

Analytical, diagnostic and therapeutic context of Pim1

• Consequently, IL-2Rbeta and Pim1 proteins were shown by Western blotting to have lower levels in NOD compared with normal B6 mice [27].
• The proviral integration site sequences were surveyed in tumor DNAs by a simple two-step PCR method [28].
• By confocal microscopy, we observed a dynamic redistribution of Pim-1 during the cell cycle, the protein moving from the nucleus and cytoplasm in interphase to the spindle poles during mitosis [29].

References