KSHV encoded LANA upregulates Pim-1 and is a substrate for its kinase activity

Bajaj, Bharat; Verma, Subhash C.; Lan, Ke; Cotter, Murray A.; Woodman, Zenda; Robertson, Erle S.

doi:10.1016/j.virol.2006.03.037

Cited by 39 publications

(47 citation statements)

References 63 publications

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“…In addition, Lu et al reported that Orf50 transcription is specifically repressed by KSHV LANA during viral latency (52). In dually infected PELs, K-LANA has been shown to suppress EBV genes by regulating the mSin3 corepressor complex (43), although K-LANA was also reported to activate EBV or human immunodeficiency virus genes (30,34), as well as cellular genes (4,40,83). The transcriptional activation and repression activities have been mapped to the amino and carboxyl termini of K-LANA, respectively (61,75,86).…”

Section: Discussionmentioning

confidence: 99%

Disruption of LANA in Rhesus Rhadinovirus Generates a Highly Lytic Recombinant Virus

Wen

Dittmer

Damania

2009

J Virol

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Section: Discussionmentioning

confidence: 99%

Disruption of LANA in Rhesus Rhadinovirus Generates a Highly Lytic Recombinant Virus

Wen

Dittmer

Damania

2009

J Virol

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“…LANA has been shown to be a substrate of PIM1 that phosphorylates LANA within the N-terminal domain. 84 In addition, a kinome wide expression library study identified activation of PIM1/PIM3 as a critical element for reactivation of a latent KSHV infection. 85 B-cell non-Hodgkin's lymphoma (NHLs) is characterized by chromosomal translocations leading to deregulation of several proto-oncogenes controlled by the immunoglobulin gene promoter and enhancer elements.…”

Section: Pim Serine/threonine Kinases In Hematologic Malignancies Andmentioning

confidence: 99%

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

Brault¹,

Gasser²,

Bracher³

et al. 2010

Haematologica

327

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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“…Overexpression of Pim-2 reduces γH2AX accumulation in DNA-damaged cells for exerting the protective effect. In the context of KSHV infection, the latent protein LANA is shown to activate Pim-1 and also act as a Pim-1 substrate (Bajaj et al, 2006), and the inactivation of LANA phosphorylation at Serine residues 205 and 206 by Pim-1 and Pim-3 kinases is required to trigger induction of KSHV lytic replication . Upon EBV latent infection, not only Pim-1 is required for LMP1-induced cell survival, but both Pim-1 and Pim-2 are also upregulated, and in turn enhance the activity of EBNA2 in driving EBVinduced cell immortalization (Rainio et al, 2005;Kim et al, 2010).…”

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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KSHV encoded LANA upregulates Pim-1 and is a substrate for its kinase activity

Cited by 39 publications

References 63 publications

Disruption of LANA in Rhesus Rhadinovirus Generates a Highly Lytic Recombinant Virus

Disruption of LANA in Rhesus Rhadinovirus Generates a Highly Lytic Recombinant Virus

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

The regulatory role of protein phosphorylation in human gammaherpesvirus associated cancers

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