Abstract
The PIM proteins, which were initially discovered as proviral insertion sites in Moloney-murine leukemia virus infection, are a family of highly homologous serine/threonine kinases that have been reported to be overexpressed in hematological malignancies and solid tumors. The PIM proteins have also been associated with metastasis and overall treatment responses and implicated in the regulation of apoptosis, metabolism, the cell cycle, and homing and migration, which makes these proteins interesting targets for anti-cancer drug discovery. The use of retroviral insertional mutagenesis and refined approaches such as complementation tagging has allowed the identification of myc, pim, and a third group of genes (including bmi1 and gfi1) as complementing genes in lymphomagenesis. Moreover, mouse modeling of human cancer has provided an understanding of the molecular pathways that are involved in tumor initiation and progression at the physiological level. In particular, genetically modified mice have allowed researchers to further elucidate the role of each of the Pim isoforms in various tumor types. PIM kinases have been identified as weak oncogenes because experimental overexpression in lymphoid tissue, prostate, and liver induces tumors at a relatively low incidence and with a long latency. However, very strong synergistic tumorigenicity between Pim1/2 and c-Myc and other oncogenes has been observed in lymphoid tissues. Mouse models have also been used to study whether the inhibition of specific PIM isoforms is required to prevent carcinogen-induced sarcomas, indicating that the absence of Pim2 and Pim3 greatly reduces sarcoma growth and bone invasion; the extent of this effect is similar to that observed in the absence of all three isoforms. This review will summarize some of the animal models that have been used to understand the isoform-specific contribution of PIM kinases to tumorigenesis.
Highlights
The PIM proteins, which were initially discovered as proviral insertion sites in Moloneymurine leukemia virus infection, are a family of highly homologous serine/threonine kinases that have been reported to be overexpressed in hematological malignancies and solid tumors
Pim1 AS A PROVIRAL INTEGRATION SITE FOR MURINE LEUKEMIA VIRUSES The proviral insertion site in Moloney-murine leukemia virus (PIM) proteins are a family of short-lived serine/threonine kinases that are highly conserved in multicellular organisms throughout evolution
The results indicated that pim1 was capable of restoring thymus cellularity to an appreciable extent and that pim1 could compensate for the lack of cytokine signaling, allowing pim1 transgenic, γc-deficient or interleukin 7 (IL-7)-deficient thymocytes to expand
Summary
Retain integration in c-myc, pim-1 enrichment of pim-2 insertion from 10% to over 50%. Untreated animals without inflammation expressed senescence markers and had low levels of Ki67 staining in similar high-grade lesions These data suggested that pim may contribute to progression rather than initiation in prostate neoplasia, indicating that pim plays a role in promoting prostate tumorigenesis in vivo, it displayed distinct oncogenic activities depending on the disease stage [33]. This line was developed by cloning the full-length human Pim cDNA downstream of the mouse albumin enhancer/promoter gene [36] and introducing this construct into fertilized oocytes of C57BL/6 mice following a standard transgenic technique When these pim transgenic mouse-derived hepatocytes were analyzed, Bad was found to be constitutively phosphorylated at Ser112 (indicating that the overexpressed PIM3 was functional) and the levels of cyclin D1 and proliferating cell nuclear antigen were increased relative to wild-type mice. Only mild hematopoietic impairments have been detected in the single Pim-KO models, which is surprising given the high evolutionary conservation of these kinases
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