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)

Vesicular stomatitis virus (VSV) is a potent inducer of apoptosis in host cells. Recently, it has been shown that two VSV products are involved in the induction of apoptosis, the matrix (M) protein, and another viral product that has yet to be identified (S. A. Kopecky et. al., J. Virol. 75:12169-12181, 2001). Comparison of recombinant viruses containing wild-type (wt) or mutant M proteins showed that wt M protein accelerates VSV-induced apoptosis in HeLa cells, while wt M protein delays apoptosis in VSV-infected BHK cells. Our hypothesis to explain these results is that both effects of M protein are due to the ability of M protein to inhibit host gene expression. This hypothesis was tested by infecting cells with an M protein mutant virus defective in the inhibition of host gene expression (rM51R-M virus) in the presence or absence of actinomycin D, another inhibitor of host gene expression. Actinomycin D accelerated induction of apoptosis of HeLa cells infected with rM51R-M virus and delayed apoptosis in BHK cells infected with rM51R-M virus, similar to the effects of wt M protein. The idea that the induction of apoptosis by M protein in HeLa cells is due to its ability to inhibit host gene expression was further tested by comparing the activation of upstream caspase pathways by M protein versus that by actinomycin D or 5,6-dichlorobenzimidazole riboside (DRB). Expression of M protein activated both caspase-8 and caspase-9-like enzymes, as did treatment with actinomycin D or DRB. Induction of apoptosis by M protein, actinomycin D, and DRB was inhibited in stably transfected HeLa cell lines that overexpress Bcl-2, an antiapoptotic protein that inhibits the caspase-9 pathway. A synthetic inhibitor of caspase-8, Z-IETD-FMK, did not inhibit induction of apoptosis by M protein, actinomycin D, or DRB. Taken together, our data support the hypothesis that the induction of apoptosis by M protein is caused by the inhibition of host gene expression and that the caspase-9 pathway is more important than the caspase-8 pathway for the induction of apoptosis by M protein and other inhibitors of host gene expression.
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PMID:Contrasting effects of matrix protein on apoptosis in HeLa and BHK cells infected with vesicular stomatitis virus are due to inhibition of host gene expression. 1266 72

Vesicular stomatitis virus (VSV) induces apoptosis by at least two mechanisms. The viral matrix (M) protein induces apoptosis via the mitochondrial pathway due to the inhibition of host gene expression. However, in some cell types, the inhibition of host gene expression by VSV expressing wild-type (wt) M protein delays VSV-induced apoptosis, indicating that another mechanism is involved. In support of this, the recombinant M51R-M (rM51R-M) virus, expressing a mutant M protein that is defective in its ability to inhibit host gene expression, induces apoptosis much more rapidly in L929 cells than do viruses expressing wt M protein. Here, we determine the caspase pathways by which the rM51R-M virus induces apoptosis. An analysis of caspase activity, using fluorometric caspase assays and Western blots, indicated that each of the main initiator caspases, caspase-8, caspase-9, and caspase-12, were activated during infection with the rM51R-M virus. The overexpression of Bcl-2, an inhibitor of the mitochondrial pathway, or MAGE-3, an inhibitor of caspase-12 activation, did not delay apoptosis induction in rM51R-M virus-infected L929 cells. However, an inhibitor of caspase-8 activity significantly delayed apoptosis induction. Furthermore, the inhibition of caspase-8 activity prevented the activation of caspase-9, suggesting that caspase-9 is activated by cross talk with caspase-8. These data indicate that VSV expressing the mutant M protein induces apoptosis via the death receptor apoptotic pathway, a mechanism distinct from that induced by VSV expressing the wt M protein.
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PMID:Vesicular stomatitis viruses expressing wild-type or mutant M proteins activate apoptosis through distinct pathways. 1576 18

Vesicular stomatitis virus (VSV) induces apoptosis via the mitochondrial pathway. The mitochondrial pathway is regulated by the Bcl-2 family of proteins, which consists of both pro- and antiapoptotic members. To determine the relative importance of the multidomain proapoptotic Bcl-2 family members Bak and Bax, HeLa cells were transfected with Bak and/or Bax small interfering RNA (siRNA) and subsequently infected with recombinant wild-type VSV. Our results showed that Bak is more important than Bax for the induction of apoptosis in this system. Bak is regulated by two antiapoptotic Bcl-2 proteins, Mcl-1, which is rapidly turned over, and Bcl-X(L), which is relatively stable. Inhibition of host gene expression by the VSV M protein resulted in the degradation of Mcl-1 but not Bcl-X(L). However, inactivation of both Mcl-1 and Bcl-X(L) was required for cells to undergo apoptosis. While inactivation of Mcl-1 was due to inhibition of its expression, inactivation of Bcl-X(L) indicates a role for one or more BH3-only Bcl-2 family members. VSV-induced apoptosis was inhibited by transfection with siRNA against Bid, a BH3-only protein that is normally activated by the cleavage of caspase-8, the initiator caspase associated with the death receptor pathway. Similarly, treatment with an inhibitor of caspase-8 inhibited VSV-induced apoptosis. These results indicate a role for cross talk from the death receptor pathway in the activation of the mitochondrial pathway by VSV.
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PMID:Vesicular stomatitis virus induces apoptosis primarily through Bak rather than Bax by inactivating Mcl-1 and Bcl-XL. 1958 33