Abstract
To characterize the mechanisms underlying apoptosis induced by viral infection, transcriptional activation of genes encoding members of the 'BH3-only' family of proteins was analysed during the course of virus infection. Among these genes, only NOXA is transcriptionally activated by vesicular stomatitis virus (VSV), sendai virus (SV), measles virus, herpes simplex virus, or dsRNA and required for efficient apoptosis of cells. Transcriptional activation of NOXA by VSV or SV is independent of p53, but requires the presence of interferon regulatory factor 1 (IRF-1), IRF-3 and cAMP-responsive element binding protein (CREB). Binding to and transactivation of the NOXA promoter by each of these transcription factors is governed by post-translational modification involving different pathways for each factor. Thus, SV infection activates IRF-3 and CREB by phosphorylation triggered by Toll like receptor 3 signalling, and a pathway involving calcium-independent phopholipase A2, respectively. In addition transactivation induced by IRF-1 during viral infection correlates with a 10 kDa increase in its molecular weight, suggesting a covalent linkage with a previously unknown regulatory polypeptide.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Apoptosis*
-
Blotting, Northern
-
Breast Neoplasms / metabolism
-
Breast Neoplasms / pathology
-
Calcium / metabolism
-
Carcinoma, Hepatocellular / metabolism
-
Carcinoma, Hepatocellular / pathology
-
Cyclic AMP Response Element-Binding Protein / metabolism*
-
Electrophoretic Mobility Shift Assay
-
Humans
-
Interferon Regulatory Factor-1 / metabolism*
-
Interferon Regulatory Factor-3 / metabolism*
-
Liver Neoplasms / metabolism
-
Liver Neoplasms / pathology
-
Measles virus / physiology
-
Phospholipases A / metabolism
-
Phosphorylation
-
Protein Processing, Post-Translational
-
Proto-Oncogene Proteins c-bcl-2 / genetics*
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
RNA Viruses / classification
-
RNA Viruses / physiology*
-
RNA, Viral / genetics*
-
Sendai virus / physiology
-
Signal Transduction
-
Simplexvirus / physiology
-
Toll-Like Receptor 3 / metabolism
-
Transcription, Genetic
-
Tumor Cells, Cultured
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism*
-
Vesicular stomatitis Indiana virus / physiology
Substances
-
Cyclic AMP Response Element-Binding Protein
-
IRF1 protein, human
-
IRF3 protein, human
-
Interferon Regulatory Factor-1
-
Interferon Regulatory Factor-3
-
PMAIP1 protein, human
-
Proto-Oncogene Proteins c-bcl-2
-
RNA, Viral
-
Toll-Like Receptor 3
-
Tumor Suppressor Protein p53
-
Phospholipases A
-
Calcium