Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P10415 (Bcl-2)
 33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kaposi's sarcoma (KS) is a vascular tumor predominantly found in the immunosuppressed. Epidemiologic studies suggest that an infective agent is the etiologic culprit. Kaposi's sarcoma-associated herpesvirus (KSHV), or human herpesvirus-8 (HHV-8), is a gamma human herpesvirus present in all epidemiologic forms of KS and also in a rare type of a B cell lymphoma, primary effusion lymphoma (PEL). In addition, this virus is present in most biopsies from human immunodeficiency virus (HIV)-associated multicentric Castleman's disease (MCD). MCD is a lymphoproliferative disorder with, like KS, a prominent microvasculature. The genome of KSHV contains the expected open reading frames (ORFs) encoding for enzymes and viral structural proteins found in other herpesviruses, but it also contains an unprecedented number of ORFs pirated during viral evolution from cellular genes. These include proteins that may alter cellular growth (e.g., Bcl-2 and cyclin homologs), induce angiogenesis (e.g., chemokine, chemokine receptor, and cytokine homologs), and regulate antiviral immunity (e.g., CD21 and interferon regulatory factor homologs). No ORF with sequence similarity to the Epstein-Barr nuclear antigens (EBNAs) and latent membrane proteins (LMPs) of Epstein-Barr virus (EBV) is present, but proteins analogous to these in structure and in latent expression are found [e.g., ORF 73 encoding for KSHV latent nuclear antigen (LNA-1) and K12 encoding for a possible latent membrane protein]. Current serologic assays confirm the strong association of infection with KSHV and risk of KS development. The mechanism of how this new virus may trigger the precipitation of KS is still unclear.
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PMID:Kaposi's sarcoma-associated herpesvirus. 970 7

The presence of human herpesvirus-8 DNA sequences, as well as an overexpression of human interleukin-6 and human cyclin D1 in myofibroblastic cells of inflammatory myofibroblastic tumor (inflammatory pseudotumor), has recently been reported. We describe the pattern of human herpesvirus-8 gene expression in five cases of pulmonary inflammatory myofibroblastic tumor. Reverse transcriptase-polymerase chain reaction (RT-PCR), with several positive and negative controls, was performed to detect mRNA of 11 open reading frames encoded by human herpesvirus-8 in lytic and latent stages of viral replicative cycle. We found molecular transcripts from ORF16, ORFK13, and ORF72 in the five cases and from ORFK2 in four of five neoplasms. The corresponding encoded proteins were human homologous oncoproteins (viral cyclin-D), inflammatory cytokines (viral IL-6), and inhibitors of apoptotic pathways (viral FLIP and viral Bcl-2), mostly expressed in a latent viral replicative stage. The rest of open reading frames examined included mainly lytic-associated genes and showed no expression. The spectrum of expressed viral genes is not the same as can be observed in Kaposi's sarcoma or multicentric Castleman's disease, suggesting that human herpesvirus-8 plays a different role in the pathogenesis of its associated diseases. These differences may be related to either cell-specific or immunologic host factors.
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PMID:Human herpesvirus-8 genes are expressed in pulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor). 1217 Jan 1

The Kaposi's sarcoma-associated herpesvirus (KSHV) (or human herpesvirus 8) open reading frame (ORF) K15 encodes a putative integral transmembrane protein in the same genomic location as latent membrane protein 2A of Epstein-Barr virus. Ectopic expression of K15 in cell lines revealed the presence of several different forms ranging in size from full length, approximately 50 kDa, to 17 kDa. Of these different species the 35- and 23-kDa forms were predominant. Mutational analysis of the initiator AUG indicated that translation initiation from this first AUG is required for K15 expression. Computational analysis indicates that the different forms detected may arise due to proteolytic cleavage at internal signal peptide sites. We show that K15 is latently expressed in KSHV-positive primary effusion lymphoma cell lines and in multicentric Castleman's disease. Using a yeast two-hybrid screen we identified HAX-1 (HS1 associated protein X-1) as a binding partner to the C terminus of K15 and show that K15 interacts with cellular HAX-1 in vitro and in vivo. Furthermore, HAX-1 colocalizes with K15 in the endoplasmic reticulum and mitochondria. The function of HAX-1 is unknown, although the similarity of its sequence to those of Nip3 and Bcl-2 infers a role in the regulation of apoptosis. We show here that HAX-1 can form homodimers in vivo and is a potent inhibitor of apoptosis and therefore represents a new apoptosis regulatory protein. The putative functions of K15 with respect to its interaction with HAX-1 are discussed.
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PMID:K15 protein of Kaposi's sarcoma-associated herpesvirus is latently expressed and binds to HAX-1, a protein with antiapoptotic function. 1175 70

Paclitaxel has significant antitumor activity in several human tumors, including Kaposi's sarcoma (KS). Human herpesvirus 8 (HHV-8) is implicated in all forms of Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD), indicating that it is a DNA tumor virus. Since it is difficult to culture cell lines derived from KS patients, we used a cell line derived from PEL (BCBL-1) to investigate whether oxidative stress is involved in the cytotoxicity of paclitaxel on the HHV-8-related tumors. We found that the generation of reactive oxygen species (ROS) in the BCBL-1 cells was increased by paclitaxel treatment, and the increase in ROS production was suppressed by antioxidants, including catalase and ascorbic acid. Moreover, ascorbic acid also attenuated the cytotoxicity induced by paclitaxel. Upon paclitaxel treatment, caspase-2, caspase-3, and caspase-8 were activated in BCBL-1 cells. Cotreatment with antioxidants did not affect caspase-2, caspase-3 or caspase-8 activation. Paclitaxel-induced apoptosis was also accompanied by an increase in the protein levels of Bax, and this effect was attenuated by antioxidants. Paclitaxel slightly decreased the expression of Bcl-2 protein, but antioxidants induced Bcl-2 protein. These results suggest that oxidative stress is only partially involved in the cytotoxicity of paclitaxel in BCBL-1 cells, and that paclitaxel-induced apoptosis of BCBL-1 cells is primarily mediated by the caspase activation pathway.
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PMID:Involvement of oxidative stress and caspase activation in paclitaxel-induced apoptosis of primary effusion lymphoma cells. 1519 89

Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with B-cell lymphomas including primary effusion lymphoma and multicentric Castleman's disease. KSHV establishes latency within B cells by modulating or mimicking the antiapoptotic Bcl-2 family of proteins to promote cell survival. Our previous BH3 profiling analysis, a functional assay that assesses the contribution of Bcl-2 proteins towards cellular survival, identified two Bcl-2 proteins, cellular Mcl-1 and viral KsBcl-2, as potential regulators of mitochondria polarization within a latently infected B-cell line, Bcbl-1. In this study, we used two novel peptide inhibitors identified in a peptide library screen that selectively bind KsBcl-2 (KL6-7_Y4eK) or KsBcl-2 and Mcl-1 (MS1) in order to decipher the relative contribution of Mcl-1 and KsBcl-2 in maintaining mitochondrial membrane potential. We found treatment with KL6-7_Y4eK and MS1 stimulated a similar amount of cytochrome c release from mitochondria isolated from Bcbl-1 cells, indicating that inhibition of KsBcl-2 alone is sufficient for mitochondrial outer membrane permiabilzation (MOMP) and thus apoptosis during a latent B cell infection. In turn, this study also identified and provides a proof-of-concept for the further development of novel KsBcl-2 inhibitors for the treatment of KSHV-associated B-cell lymphomas via the targeting of latently infected B cells.
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PMID:Selective peptide inhibitors of antiapoptotic cellular and viral Bcl-2 proteins lead to cytochrome c release during latent Kaposi's sarcoma-associated herpesvirus infection. 2645 86