Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death

Pircher, Tony J.; Shuqing, Zhao; Geiger, Justin N.; Joneja, Bhavana; Wojchowski, Don M.

doi:10.1038/sj.onc.1203684

Cited by 55 publications

(41 citation statements)

References 47 publications

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“…Interestingly, cellular protection was associated with nuclear localization of a large fraction of the short (p33) but not the long (p44) PIM1 isoform suggesting the existence of functionally important isoformspecific cellular substrates. 40 A PIM1 consensus site (RKR-RQTSM) was found in the cell cycle regulator p21 Cip1/WAF1 (CDKN1A). PIM1 associated with and phosphorylated p21…”

mentioning

confidence: 99%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

335

413

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The online version of this article has a Supplementary Appendix.The identification as cooperating targets of Proviral Integrations of Moloney virus in murine lymphomas suggested early on that PIM serine/threonine kinases play an important role in cancer biology. Whereas elevated levels of PIM1 and PIM2 were mostly found in hematologic malignancies and prostate cancer, increased PIM3 expression was observed in different solid tumors. PIM kinases are constitutively active and their activity supports in vitro and in vivo tumor cell growth and survival through modification of an increasing number of common as well as isoform-specific substrates including several cell cycle regulators and apoptosis mediators. PIM1 but not PIM2 seems also to mediate homing and migration of normal and malignant hematopoietic cells by regulating chemokine receptor surface expression. Knockdown experiments by RNA interference or dominant-negative acting mutants suggested that PIM kinases are important for maintenance of a transformed phenotype and therefore potential therapeutic targets. Determination of the protein structure facilitated identification of an increasing number of potent small molecule PIM kinase inhibitors with in vitro and in vivo anticancer activity. Ongoing efforts aim to identify isoform-specific PIM inhibitors that would not only help to dissect the kinase function but hopefully also provide targeted therapeutics. Here, we summarize the current knowledge about the role of PIM serine/threonine kinases for the pathogenesis and therapy of hematologic malignancies and solid cancers, and we highlight structural principles and recent progress on small molecule PIM kinase inhibitors that are on their way into first clinical trials. Haematologica 2010;95:1004-1015. doi:10.3324/haematol.2009 This is an open-access paper. ABSTRACTin blast crisis. 6 Abundant levels of PIM1 were found in hematopoietic cells. Moreover, sustained PIM1 expression was induced by cytokines that signal through structurally related receptors such as IL-3, GM-CSF, G-CSF or Subsequently, several studies have documented that PIM1 is a major downstream target of the signal transducer and activator of transcription (STATs) induced by a large variety of additional receptors such as IL-2, IL-7, IL-9, IFNγ, EPO, FLT3 or TPO.7 PIM1 expression is not only regulated at the transcriptional, but also at the posttranscriptional, translational and posttranslational levels ( Figure 1). Other studies have shown that PIM1 kinase is significantly protected from proteasomal degradation by heat shock proteins (Hsp70, Hsp90). 8,9 Moreover, it has been proposed that micro-RNAs, miR-1 and miR-210, might be implicated in regulation of PIM1 expression. 10,11 Germline inactivation of the PIM1 gene was associated with a mild phenotype as PIM1 deficient mice are ostensibly normal, healthy and fertile. However, subtle functional defects of the hematopoietic system have been identified: PIM1 -/-mice showed erythrocytic microcytosis and PIM1-/-B cells and bone marrow-derived mast c...

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mentioning

confidence: 99%

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

335

413

View full text Add to dashboard Cite

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“…pim-1 expression is induced by a variety of cytokines, growth factors, and mitogens including IL-2, IL-3, IL-6, IL-9, IL-12, IL-15, erythropoietin, GM-CSF, G-CSF, IFNs ␣ and ␥, prolactin, Con A, PMA, and anti-CD3 Abs (44 -52). Moreover, in the FDCP1 myeloid cell line, constitutive expression of an exogenous pim-1 gene can inhibit apoptosis caused by cytokine deprivation, DNA-damaging agents, and Bax expression (53)(54)(55). In normal cells, the expression of a pim-1 transgene can suppress the spontaneous ex vivo apoptosis of peripheral T cells as well as the dexamethasoneinduced apoptosis of thymocytes (56).…”

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confidence: 99%

CD40 Signaling in B Cells Regulates the Expression of the Pim-1 Kinase Via the NF-κB Pathway

Zhu

Ramirez

Lee

et al. 2002

The Journal of Immunology

109

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The ability of CD40 signaling to regulate B cell growth, survival, differentiation, and Ig class switching involves many changes in gene expression. Using cDNA expression arrays and Northern blotting, we found that CD40 signaling increased the mRNA levels for pim-1, a protooncogene that encodes a serine/threonine protein kinase. Subsequent experiments showed that CD40 engagement also increased both Pim-1 protein levels and Pim-1 kinase activity in B cells. 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-κB. Inhibiting the activation of NF-κB, either by treating cells with a chemical inhibitor, BAY11-7082, or by inducibly expressing a superrepressor form of IκBα, significantly impaired the ability of CD40 to increase Pim-1 protein levels. Because Pim-1 expression is associated with cell proliferation and survival, we asked whether this correlated with the ability of CD40 signaling to prevent anti-IgM-induced growth arrest in the WEHI-231 murine B cell line, a model for Ag-induced clonal deletion. We found that the anti-IgM-induced growth arrest in WEHI-231 cells correlated with a substantial decrease in Pim-1 levels. In contrast, culturing WEHI-231 cells with either anti-CD40 Abs or with the B cell mitogen LPS, both of which prevent the anti-IgM-induced growth arrest, also prevented the rapid decline in Pim-1 levels. This suggests that Pim-1 could regulate the survival and proliferation of B cells.

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“…Among them, Pim-1 is able to phosphorylate itself, and there are several substrates have been identified, including p21, Cdc25A, NuMA for driving cell proliferation through the transition of G1/S and G2/M phase, and protecting cell from genotoxin-induced death (Pircher et al, 2000). In contrast, Pim-2 kinase is an essential component of the DNA-damage response, and is an upstream activator of the phosphorylation of pro-survival/anti-apoptotic factors E2F-1 and ATM (Zirkin et al, 2013).…”

Section: Phosphorylation-mediated Viral Manipulation Of Dna Damage Rementioning

confidence: 99%

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

et al. 2017

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Activation of specific sets of protein kinases by intracellular signal molecules has become more and more apparent in the past decade. Phosphorylation, one of key posttranslational modification events, is activated by kinase or regulatory protein and is vital for controlling many physiological functions of eukaryotic cells such as cell proliferation, differentiation, malignant transformation, and signal transduction mediated by external stimuli. Moreovers, the reversible modification of phosphorylation and dephosphorylation can result in different features of the target substrate molecules including DNA binding, protein-protein interaction, subcellular location and enzymatic activity, and is often hijacked by viral infection. Epstein-Barr virus (EBV) and Kaposi's sarcomaassociated herpesvirus (KSHV), two human oncogenic gamma-herpesviruses, are shown to tightly associate with many malignancies. In this review, we summarize the recent progresses on understanding of molecular properties and regulatory modes of cellular and viral proteins phosphorylation influenced by these two tumor viruses, and highlight the potential therapeutic targets and strategies against their related cancers.

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Pim-1 kinase protects hematopoietic FDC cells from genotoxin-induced death

Cited by 55 publications

References 47 publications

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers

CD40 Signaling in B Cells Regulates the Expression of the Pim-1 Kinase Via the NF-κB Pathway

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

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