Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nucleophosmin (NPM, B23) is an abundant nucleolar phosphoprotein involved in ribosome biogenesis, and interacts with tumor suppressor proteins p53 and Rb. Here we show that NPM is a UV damage response protein that undergoes nucleoplasmic redistribution and regulates p53 and HDM2 levels and their interaction. By utilizing RNAi approaches and analyses of endogenous and ectopically expressed proteins, we demonstrate that NPM binds HDM2 and acts as a negative regulator of p53-HDM2 interaction. Viral stress, enforced by expression of Kaposi's sarcoma virus K cyclin, causes NPM redistribution, K cyclin-NPM association, and p53 stabilization by dissociation of HDM2-p53 complexes. The results demonstrate novel associations of HDM2 and K cyclin with NPM and implicate NPM as a crucial controller of p53 through inhibition of HDM2.
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PMID:Nucleolar protein NPM interacts with HDM2 and protects tumor suppressor protein p53 from HDM2-mediated degradation. 1514 54

In immunocompromised patients, infection with Kaposi's sarcoma-associated herpesvirus (KSHV) can give rise to Kaposi's sarcoma and several lymphoproliferative disorders. In these tumors, KSHV establishes a latent infection in many of the rapidly proliferating and morphologically abnormal cells. Only a few viral gene products are expressed by the latent virus, and one of the best characterized is the latency-associated nuclear antigen (LANA), a nuclear protein required for the maintenance of viral episomal DNA in the dividing host cell. LANA can also activate or repress an assortment of cellular and viral promoters and may contribute to pathogenesis by allowing the proliferation and survival of host cells. Here we show that activation of the human E2F1 and cyclin-dependent kinase-2 (CDK2) promoters requires elements from both the N- and C-terminal regions of LANA. Deletion of the first 22 amino acids, which are necessary for episome tethering, does not affect nuclear localization but significantly reduces transactivation. Within the deleted peptide, we have identified a short sequence, termed the chromatin-binding motif (CBM), that binds tightly to interphase and mitotic chromatin. A second chromatin-binding activity resides in the C terminus but is not sufficient for optimal transactivation. Alanine substitutions within the CBM reveal a close correlation between the transactivation and chromatin binding activities, implying a mechanistic link. In contrast to promoter activation, we find that the 223 amino acids of the LANA C terminus are sufficient to inhibit p53-mediated activation of the human BAX promoter, indicating that the CBM is not required for all transcription-related functions.
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PMID:Transcriptional activation by the Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen is facilitated by an N-terminal chromatin-binding motif. 1533 40

All known DNA tumor viruses are known to target and inactivate two main cell cycle regulatory proteins, retinoblastoma protein (pRb) and p53. Inactivation of pRb promotes host cell cycle progression into S phase, and inactivation of p53 promotes cell immortalization. The DNA tumor virus Kaposi's sarcoma associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA) was shown to target and inactivate pRb as well as p53. In this report we provide evidence that these functions are conserved in the homologous protein encoded by the related gammaherpesvirus herpesvirus saimiri (HVS). ORF73, the HVS homologue of LANA, is shown to bind both p53 and pRb in vitro and in vivo, to colocalize with p53 in human T cells infected with HVS, and in cells overexpressing both ORF73 and p53, as well as to adversely influence pRB/E2F and p53 transcriptional regulation. The C terminus of LANA, the region most highly conserved in ORF73, is shown to be responsible for both pRb and p53 interactions, supporting the hypothesis that these functions are conserved in both homologues. Finally, the region of p53 targeted by LANA (and ORF73) maps to the domain required for tetramerization. However, preliminary cross-linking studies do not detect disruption of p53 tetramerization by either LANA or HVS-encoded ORF73, suggesting that p53 inactivation may be by a mechanism independent of tetramer disruption.
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PMID:ORF73 of herpesvirus saimiri, a viral homolog of Kaposi's sarcoma-associated herpesvirus, modulates the two cellular tumor suppressor proteins p53 and pRb. 1536

Latently infected Kaposi's sarcoma-associated herpes-virus (KSHV)-associated tumor cells have both endothelial and lymphoid origins and express a limited set of latent viral genes. One such gene, ORF73, encodes the latency-associated nuclear antigen (LANA), a multifunctional protein that plays roles in viral DNA replication, episome maintenance, and transcriptional regulation. LANA interacts with cellular proteins involved in transcriptional regulation such as the tumor suppressors, retinoblastoma (Rb) and p53, and RING3 family members. Although several reports about specific LANA-regulated promoters exist, only limited data are available that address how LANA expression in KSHV-infected cells globally affects cellular gene expression, thereby potentially contributing to KSHV pathogenicity. To investigate this question, we generated an Epstein-Barr virus-negative Burkitts lymphoma line that expresses LANA from a tetracycline-inducible promoter (BJAB/Tet-On/LANA), and we performed microarray-based gene expression profiling. Expression profiling at different time points post-induction revealed that 186 genes were activated or repressed over 2-fold in the presence of LANA. Of these genes, 41 are regulated in the Rb/E2F pathway, whereas 7 are related to p53 signaling. To determine whether these gene expression changes translate into LANA-dependent changes in cell cycle regulation, we overexpressed p16 INK4a, a CDK4/6 inhibitor that efficiently induces cell cycle arrest in Rb-positive cells. Under these conditions, LANA expression protects lymphoid cells from p16 INK4a-induced cell cycle arrest and induces S-phase entry.
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PMID:The latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus modulates cellular gene expression and protects lymphoid cells from p16 INK4A-induced cell cycle arrest. 1552 42

Kaposi sarcoma-associated herpesvirus (KSHV) is linked with all clinical forms of Kaposi sarcoma and several lymphoproliferative disorders. Like other herpesviruses, KSHV becomes latent in the infected cells, expressing only a few genes that are essential for the establishment and maintenance of its latency and for the survival of the infected cells. Inhibiting the expression of these latent genes should lead to eradication of herpesvirus infection. All currently available drugs are ineffective against latent infection. Here we show, for the first time to our knowledge, that latent infection with KSHV in B lymphocytes can be terminated by glycyrrhizic acid (GA), a triterpenoid compound earlier shown to inhibit the lytic replication of other herpesviruses. We demonstrate that GA disrupts latent KSHV infection by downregulating the expression of latency-associated nuclear antigen (LANA) and upregulating the expression of viral cyclin and selectively induces cell death of KSHV-infected cells. We show that reduced levels of LANA lead to p53 reactivation, an increase in ROS, and mitochondrial dysfunction, which result in G1 cell cycle arrest, DNA fragmentation, and oxidative stress-mediated apoptosis. Latent genes are involved in KSHV-induced oncogenesis, and strategies to interfere with their expression might prove useful for eradicating latent KSHV infection and have future therapeutic implications.
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PMID:Glycyrrhizic acid alters Kaposi sarcoma-associated herpesvirus latency, triggering p53-mediated apoptosis in transformed B lymphocytes. 1576 43

All known gamma2-herpesviruses encode a cyclin homolog with significant homology to mammalian D-type cyclins. The murine gammaherpesvirus 68 (gammaHV68) viral cyclin (v-cyclin) has been shown to be oncogenic when expression is targeted to thymocytes in transgenic mice and to be critical for virus reactivation from latency. Here, we investigate the interaction of the gammaHV68 v-cyclin with cellular cyclin-dependent kinases (cdks). We show that, in contrast to the Kaposi's sarcoma-associated herpesvirus (KSHV) v-cyclin, the gammaHV68 v-cyclin preferentially interacts with cdk2 and cdc2 but does not interact with either cdk4 or cdk6. Mutation of conserved residues, predicted to be involved in cdk binding based on the gammaHV68 v-cyclin:cdk2 crystal structure, resulted in the loss of both cdk binding and the ability to mediate phosphorylation of substrates. Like the KSHV v-cyclin, the gammaHV68 v-cyclin appears to confer expanded substrate specificity to the cellular cdk binding partners. As expected, the gammaHV68 v-cyclin:cdk complexes are able to target phosphorylation of histone H1, the retinoblastoma protein (pRb), and p27(Kip1) as assessed using in vitro kinase assays. Notably, hyperphosphorylation of pRb was observed during wt gammaHV68 replication in serum-starved murine fibroblasts, but not in cells that were either mock-infected or infected with a v-cyclin null gammaHV68. In addition, infection of serum-starved murine fibroblasts also results in a v-cyclin-dependent increase in cdk2-associated kinase activity and a concomitant decrease in the levels of p27(Kip1). Taken together, the latter studies served to validate the results of the in vitro kinase assays. Finally, in vitro kinase assays revealed that the gammaHV68 v-cyclin:cdk complexes can also phosphorylate p21(Cip1), Bcl-2, and p53. The latter suggests that, at least in vitro, the gammaHV68 v-cyclin exhibits functional characteristics of both cyclin E and cyclin A.
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PMID:Characterization of murine gammaherpesvirus 68 v-cyclin interactions with cellular cdks. 1610 93

Human immunodeficiency virus (HIV)-associated lymphomas include: (1) lymphomas also occurring, although sporadically, in the absence of HIV infection. The vast majority of these lymphomas are high-grade B-cell lymphomas: Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) with centroblastic (CB) features and DLBCL with immunoblastic (IBL) features; (2) unusual lymphomas occurring more specifically in HIV-positive patients and include two rare entities, namely 'primary effusion lymphoma' (PEL) and 'plasmablastic lymphoma' of the oral cavity. The pathological heterogeneity of acquired immunodeficiency syndrome-associated non-Hodgkin's lymphomas (AIDS-NHL) reflects the heterogeneity of their associated molecular lesions. In AIDS-BL, the molecular lesions involve activation of cMYC, inactivation of P53, and infection with Epstein-Barr virus (EBV). AIDS-IBL infected with EBV are characterised by frequent expression of latent membrane protein 1--an EBV oncoprotein. The biological heterogeneity of AIDS-NHL is highlighted by their histogenetic differences. Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8)-associated lymphomas, which often develop in persons with advanced AIDS, present predominantly as PEL. KSHV/HHV8 has also been recently detected in solid extracavitary-based lymphomas. The KSHV/HHV8-associated solid lymphomas are (1) unusual lymphomas that occur more specifically in HIV-positive patients; (2) extracavitary and arise in nodal and/or extranodal sites; and (3) histologically, they usually display a PEL-like morphology and plasma cell-related phenotype.
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PMID:AIDS-related lymphomas: from pathogenesis to pathology. 1611 21

Kaposi sarcoma (KS) remains the most common AIDS-associated malignancy worldwide. In sub-Saharan Africa especially, this aggressive endothelial-cell tumor is a cause of widespread morbidity and mortality. Infection with Kaposi sarcoma-associated herpesvirus (KSHV) is now known to be an etiologic force behind KS and primary-effusion lymphoma (PEL). Over time, KSHV has pirated many human genes whose products regulate angiogenesis, inflammation, and the cell cycle. One of these, the KSHV vGPCR, is a lytic product that is a constitutively active homolog of the IL-8 receptor. Although it is considered a viral oncogene and causes KS-like lesions in mice, vGPCR expression results in cell-cycle arrest of KSHV-infected PEL cells. In the present study, we show that this arrest is mediated by p21 in a p53-independent manner; the resulting Cdk2 inhibition decreases the efficiency of chemical induction of KSHV lytic transcripts ORF 50 and 26. Importantly, Cdk2 activity is also essential for replication in other human herpesviruses. The ability of vGPCR to delay or abort KSHV replication may explain how despite being a lytic product, this potent signaling molecule has a vital role in tumor formation via its induction of various KS-associated cytokines.
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PMID:KSHV G protein-coupled receptor inhibits lytic gene transcription in primary-effusion lymphoma cells via p21-mediated inhibition of Cdk2. 1615 Sep 42

LANA2 is a latent protein detected in Kaposi's sarcoma-associated herpesvirus (KSHV)-infected B cells that inhibits p53-dependent transcriptional transactivation and apoptosis and PKR-dependent apoptosis, suggesting an important role in the transforming activity of the virus. It has been reported that LANA2 localizes into the nucleus of both KSHV-infected B cells and transiently transfected HeLa cells. In this study, we show that LANA2 is a nucleocytoplasmic shuttling protein that requires a Rev-type nuclear export signal located in the C-terminus to direct the protein to the cytoplasm, through an association with the export receptor CRM1. In addition, a functional protein kinase B (PKB)/Akt phosphorylation motif partially overlapping with the nuclear export signal was identified. Nuclear exclusion of LANA2 was negatively regulated by the phosphorylation of threonine 564 by Akt. The ability of LANA2 to shuttle between nucleus and cytoplasm has implications for the function of this viral protein.
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PMID:Identification of a nuclear export signal in the KSHV latent protein LANA2 mediating its export from the nucleus. 1621 30

Kaposi's sarcoma-associated herpesvirus (KSHV) is a lymphotropic DNA tumor virus that induces Kaposi's sarcoma and AIDS-related primary effusion lymphoma. KSHV open reading frame 50 and K8 genes in early viral lytic infection express, respectively, a tricistronic and a bicistronic pre-mRNA, which undergo alternative splicing to create two major spliced mRNA isoforms, alpha and beta, by inclusion (beta) or exclusion (alpha) of an intron at nucleotides 75563 to 75645. This intron contains some suboptimal features, which cause the intron 5' splice site (ss) to interact weakly with U1 snRNA and the 3' ss to bind a U2 auxiliary factor, U2AF, with low affinity. Optimization of this intron in K8 (K8 intron 2) promoted the interaction of the 5' ss with U1 and the 3' ss with U2AF, resulting in a substantial increase in intron splicing. Splicing of K8 intron 2 has also been shown to be stimulated by the splicing of a downstream intron. This was confirmed by the insertion of a human beta-globin intron into the K8beta exon 3-exon 4 splice junction, which promoted splicing of K8beta intron 2 and conversion of the K8beta mRNA to the K8alpha mRNA that encodes a K-bZIP protein. Intron 2 contains a premature termination codon, yet the K8beta mRNA is insensitive to nonsense-mediated mRNA decay, suggesting that the truncated K8beta protein may have a biological function. Indeed, although the truncated K8beta protein is missing only a C-terminal leucine zipper domain from the K-bZIP, its expression antagonizes the ability of the K-bZIP to induce p53 and p21 and blocks K-bZIP-CDK2 interaction through interfering K8alpha mRNA production.
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PMID:Kaposi's sarcoma-associated herpesvirus K8beta is derived from a spliced intermediate of K8 pre-mRNA and antagonizes K8alpha (K-bZIP) to induce p21 and p53 and blocks K8alpha-CDK2 interaction. 1625 56


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