Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our laboratory has recently demonstrated constitutive activation of the Notch signaling pathway in Kaposi's sarcoma tumor cells. As endothelial cells (EC) are believed to be the progenitor of these tumor cells, this study was designed to examine the effect of Notch activation on normal human EC. Recent reports suggest Notch activation induces EC growth arrest, and that this growth arrest may be linked to the establishment or maintenance of EC quiescence, the phenotype seen in contact-inhibited EC lining the vasculature. To gain further insight into Notch activation and quiescence, we first confirmed that Notch activation induced EC growth arrest. Next, we examined Notch activation in confluent, growth arrested EC (mimicking the cells lining the vasculature). In contrast to previous reports, we found confluent EC possess lower levels of activated Notch compared to proliferating control cells. Interestingly, these cells express elevated levels of Hes-1 protein (an immediate downstream target of Notch signaling) despite decreased Notch activation. Under these conditions, Hes-1 expression was mediated, at least in part, by a Notch-independent mechanism involving c-jun N-terminal protein kinase (JNK) signaling. This is the first report, to our knowledge, that JNK signaling can modulate Hes-1 expression in a Notch-independent manner.
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PMID:Notch-independent regulation of Hes-1 expression by c-Jun N-terminal kinase signaling in human endothelial cells. 1673 96

The oncogenic herpesvirus, Kaposi's sarcoma-associated herpesvirus, also identified as human herpesvirus 8, contains genes producing proteins that control transcription and influence cell signaling. Open reading frame 36 (ORF36) of this virus encodes a serine/threonine protein kinase, which is designated the viral protein kinase (vPK). Our recent efforts to elucidate the role of vPK in the viral life cycle have focused on identifying viral protein substrates and determining the effects of vPK-mediated phosphorylation on specific steps in viral replication. The vPK gene was transcribed into 4.2-kb and 3.6-kb mRNAs during the early and late phases of viral reactivation. vPK is colocalized with viral DNA replication/transcription compartments as marked by a polymerase processivity factor, and K-bZIP, a protein known to bind the viral DNA replication origin (Ori-Lyt) and to regulate viral transcription. The vPK physically associated with and strongly phosphorylated K-bZIP at threonine 111, a site also recognized by the cyclin-dependent kinase Cdk2. Both K-bZIP and vPK were corecruited to viral promoters targeted by K-bZIP as well as to the Ori-Lyt region. Phosphorylation of K-bZIP by vPK had a negative impact on K-bZIP transcription repression activity. The extent of posttranslational modification of K-bZIP by sumoylation, a process that influences its repression function, was decreased by vPK phosphorylation at threonine 111. Our data thus identify a new role of vPK as a modulator of viral transcription.
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PMID:Kaposi's sarcoma-associated herpesvirus-encoded protein kinase and its interaction with K-bZIP. 1710 53

The seminal experiments of George and Eva Klein helped to define the two life cycles of Epstein-Barr Virus (EBV), namely latency and lytic or productive infection. Their laboratories described latent nuclear antigens expressed during latency and discovered several chemicals that activated the viral lytic cycle. The mechanism of the switch between latency and the lytic cycle of EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) can be studied in cultured B cell lines. Lytic cycle activation of EBV is controlled by two viral transcription factors, ZEBRA and Rta. The homologue of Rta encoded in ORF50 is the lytic cycle activator of KSHV. Control of the lytic cycle can be divided into two distinct phases. Upstream events control expression of the virally encoded lytic cycle activator genes. Downstream events represent tasks carried out by the viral proteins in driving expression of lytic cycle genes and lytic viral DNA replication. In this chapter, we report three recent groups of experiments relating to upstream and downstream events. Azacytidine (AzaC) is a DNA methyltransferase inhibitor whose lytic cycle activation capacity was discovered by G. Klein and coworkers. We find that AzaC rapidly activates the EBV lytic cycle but does not detectably alter DNA methylation or histone acetylation on the promoters of the EBV lytic cycle activator genes. AzaC probably acts via a novel, yet to be elucidated, mechanism. The lytic cycle of both EBV and KSHV can be activated by sodium butyrate (NaB), a histone deacetylase inhibitor whose activity in disrupting latency was also discovered by G. Klein and coworkers. Activation of EBV by NaB requires protein synthesis; activation of KSHV is independent of protein synthesis. Thus, NaB works by a different pathway on the two closely related viruses. ZEBRA, the major downstream mediator of EBV lytic cycle activation is both a transcription activator and an essential replication protein. We show that phosphorylation of ZEBRA at its casein kinase 2 (CK2) site separates these two functions. Phosphorylation by CK2 is required for ZEBRA to activate lytic replication but not to induce expression of early lytic cycle genes. We discuss a number of unsolved mysteries about lytic cycle activation which should provide fertile territory for future research.
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PMID:Lytic cycle switches of oncogenic human gammaherpesviruses. 1741 42

Chromosome loss or gain is associated with a large number of solid cancers, providing genomic plasticity and thus adaptability to cancer cells. Numerical centrosome abnormalities arising from centrosome over-duplication or failed cytokinesis are a recognized cause of aneuploidy. In higher eukaryotic cells, the centrosome duplicates only once per cell cycle to ensure the formation of a bipolar mitotic spindle that orchestrates the balanced distribution of the sister chromatids to the respective daughter cells. Here we delineate the events that allow abnormal centrosome duplication, resulting in mitotic errors and incorrect chromosome segregation in cells with sustained cyclin-dependent kinase (CDK) activity. We have identified NPM1 as a substrate for CDK6 activated by the Kaposi's sarcoma herpesvirus (KSHV) D-type cyclin and shown that p53-driven apoptosis occurs downstream of NPM1 phosphorylation as a checkpoint mechanism that prevents accumulation of cells with supernumerary centrosomes. Our findings provide evidence that abnormal chromosome segregation in KSHV-infected cells is a direct consequence of NPM1 phosphorylation and predict that genomic instability is an inevitable consequence of latent KSHV infection.
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PMID:p53-Driven apoptosis limits centrosome amplification and genomic instability downstream of NPM1 phosphorylation. 1845 40

Kaposi's sarcoma-associated herpesvirus (KSHV) has been linked to the development of Kaposi's sarcoma, a major AIDS-associated malignancy, and to hematologic malignancies, including primary effusion lymphoma and multicentric Castleman's disease. Like other herpesviruses, KSHV is capable of both latent and lytic replication. Understanding the molecular details associated with this transition from latency to lytic replication is key to controlling virus spread and can affect the development of intervention strategies. Here, we report that Kruppel-associated box domain-associated protein-1 (KAP-1)/transcriptional intermediary factor 1beta, a cellular transcriptional repressor that controls chromosomal remodeling, participates in the process of switching viral latency to lytic replication. Knockdown of KAP-1 by small interfering RNA leads to KSHV reactivation mediated by K-Rta, a key transcriptional regulator. In cells harboring latent KSHV, KAP-1 was associated with the majority of viral lytic-gene promoters. K-Rta overexpression induced the viral lytic cycle with concomitant reduction of KAP-1 binding to viral promoters. Association of KAP-1 with heterochromatin was modulated by both sumoylation and phosphorylation. During lytic replication of KSHV, KAP-1 was phosphorylated at Ser(824). Several lines of evidence directly linked the viral protein kinase to this post-translational modification. Additional studies showed that this phosphorylation of KAP-1 produced a decrease in its sumoylation, consequently decreasing the ability of KAP-1 to condense chromatin on viral promoters. In summary, the cellular transcriptional repressor KAP-1 plays a role in regulating KSHV latency, and viral protein kinase modulates the chromatin remodeling function of this repressor.
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PMID:Kruppel-associated box domain-associated protein-1 as a latency regulator for Kaposi's sarcoma-associated herpesvirus and its modulation by the viral protein kinase. 1958 88

During latent infection, latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) plays important roles in episomal persistence and replication. Several host factors are associated with KSHV latent replication. Here, we show that the catalytic subunit of DNA protein kinase (DNA-PKcs), Ku70, and Ku86 bind the N-terminal region of LANA. LANA was phosphorylated by DNA-PK and overexpression of Ku70, but not Ku86, impaired transient replication. The efficiency of transient replication was significantly increased in the HCT116 (Ku86 +/-) cell line, compared to the HCT116 (Ku86 +/+) cell line, suggesting that the DNA-PK/Ku complex negatively regulates KSHV latent replication.
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PMID:DNA-PK/Ku complex binds to latency-associated nuclear antigen and negatively regulates Kaposi's sarcoma-associated herpesvirus latent replication. 2030 34

Kaposi's sarcoma-associated herpes virus (KSHV)-encoded latency-associated nuclear antigen (LANA) protein has been reported to interact with glycogen synthase kinase 3beta (GSK-3beta) and to negatively regulate its activity, leading to stimulation of GSK-3beta-dependent beta-catenin degradation. We show here that the I-mfa domain proteins, HIC (human I-mfa domain-containing protein) and I-mfa (inhibitor of MyoD family a), interacted in vivo with LANA through their C-terminal I-mfa domains. This interaction affected the intracellular localization of HIC, inhibited the LANA-dependent transactivation of a beta-catenin-regulated reporter construct, and decreased the level of the LANA.GSK-3beta complex. These data reveal for the first time that I-mfa domain proteins interact with LANA and negatively regulate LANA-mediated activation of Wnt signaling-dependent transcription by inhibiting the formation of the LANA.GSK-3beta complex.
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PMID:Human I-mfa domain proteins specifically interact with KSHV LANA and affect its regulation of Wnt signaling-dependent transcription. 2041 16

RNA helicase A (RHA) containing the DExH motif is a human homolog of maleless protein that regulates expression of genes located in the Drosophila X chromosome during dosage compensation. RHA exerts helicase activity that unwinds double-stranded RNA and DNA to a single-strand form. The protein acts as a bridging factor mediating interactions of CBP/p300 and RNA pol II, and consequently affects gene expression. Kaposi's sarcoma-associated herpesvirus (KSHV) is a member of the gamma-herpesvirus subfamily that causes several disorders. The majority of herpesviruses commonly encode predicted viral protein kinases. KSHV open reading frame 36 (ORF36) codes for protein kinase domains, and functions as a serine/threonine protein kinase. KSHV ORF36 is classified as a late gene, as it is expressed during lytic replication and localized in the nuclei of KSHV-infected cells. Recent studies show that viral protein kinase (vPK) interacts with cellular proteins. In this study, we determined the cellular localization of vPK in KSHV-infected BCBL-1 cells using confocal microscopy. Proteomic analysis indicates that cellular proteins interacted with vPK, and co-immunoprecipitation reactions further reveal interactions between vPK and RHA. Moreover, KSHV vPK appeared to regulate the transcriptional activation of Cre promoter, and plays an important role in cellular transcription of RHA.
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PMID:Kaposi's sarcoma-associated herpesvirus viral protein kinase interacts with RNA helicase a and regulates host gene expression. 2043 53

The Kaposi's sarcoma-associated herpesvirus (KSHV) contains several open reading frames (ORFs) that encode proteins capable of initiating and modulating cellular signaling pathways. Among them is ORF K15, encoding a 12-transmembrane-spanning protein with a cytoplasmic C-terminal domain. Through conserved binding motifs, such as Src homology 2 (SH2) and SH3 binding sites, K15 interacts with cellular proteins, activates the NF-kappaB, MEK/Erk, and Jun N-terminal protein kinase (JNK) pathways, and induces the expression of several inflammatory and angiogenic genes. In this study, we investigated the role of an SH3 domain binding site centered on a PPLP motif in K15. We screened libraries of cellular SH3 domains to identify signaling molecules interacting with the KSHV PPLP motif. We found its affinities for two Src kinase family members, Lyn and Hck, to exceed those of other viral proteins. While the SH2 binding motif YEEV is essential for the inflammatory response induced by KSHV K15, recruitment of Lyn and Hck to the K15 PPLP motif seems to be dispensable for this inflammatory response. However, the PPLP motif is essential for the decrease in B-cell receptor-mediated signaling induced by K15, as measured by calcium mobilization assays.
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PMID:Role of the Kaposi's sarcoma-associated herpesvirus K15 SH3 binding site in inflammatory signaling and B-cell activation. 2053 55

COX-2 has been implicated in Kaposi's sarcoma-associated herpesvirus (KSHV) latency and pathogenesis (A. George Paul, N. Sharma-Walia, N. Kerur, C. White, and B. Chandran, Cancer Res. 70:3697-3708, 2010; P. P. Naranatt, H. H. Krishnan, S. R. Svojanovsky, C. Bloomer, S. Mathur, and B. Chandran, Cancer Res. 64:72-84, 2004; N. Sharma-Walia, A. G. Paul, V. Bottero, S. Sadagopan, M. V. Veettil, N. Kerur, and B. Chandran, PLoS Pathog. 6:e1000777, 2010; N. Sharma-Walia, H. Raghu, S. Sadagopan, R. Sivakumar, M. V. Veettil, P. P. Naranatt, M. M. Smith, and B. Chandran, J. Virol. 80:6534-6552, 2006). However, the precise regulatory mechanisms involved in COX-2 induction during KSHV infection have never been explored. Here, we identified cis-acting elements involved in the transcriptional regulation of COX-2 upon KSHV de novo infection. Promoter analysis using human COX-2 promoter deletion and mutation reporter constructs revealed that nuclear factor of activated T cells (NFAT) and the cyclic AMP (cAMP) response element (CRE) modulate KSHV-mediated transcriptional regulation of COX-2. Along with multiple KSHV-induced signaling pathways, infection-induced prostaglandin E(2) (PGE(2)) also augmented COX-2 transcription. Infection of endothelial cells markedly induced COX-2 expression via a cyclosporine A-sensitive, calcineurin/NFAT-dependent pathway. KSHV infection increased intracellular cAMP levels and activated protein kinase A (PKA), which phosphorylated the CRE-binding protein (CREB) at serine 133, which probably led to interaction with CRE in the COX-2 promoter, thereby enhancing COX-2 transcription. PKA selective inhibitor H-89 pretreatment strongly inhibited CREB serine 133, indicating the involvement of a cAMP-PKA-CREB-CRE loop in COX-2 transcriptional regulation. In contrast to phosphatidylinositol 3-kinase and protein kinase C, inhibition of FAK and Src effectively reduced KSHV infection-induced COX-2 transcription and protein levels. Collectively, our study indicates that mediation of COX-2 transcription upon KSHV infection is a paradigm of a complex regulatory milieu involving the interplay of multiple signal cascades and transcription factors. Intervention at each step of COX-2/PGE(2) induction can be used as a potential therapeutic target to treat KSHV-associated neoplasm and control inflammatory sequels of KSHV infection.
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PMID:NFAT and CREB regulate Kaposi's sarcoma-associated herpesvirus-induced cyclooxygenase 2 (COX-2). 2094 63


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