1. Inactivation of mammalian target of rapamycin increases STAT1 nuclear content and transcriptional activity in alpha4- and protein phosphatase 2A-dependent fashion.
- Author
-
Fielhaber JA, Han YS, Tan J, Xing S, Biggs CM, Joung KB, and Kristof AS
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Apoptosis genetics, Apoptosis immunology, Cell Line, Cell Nucleus genetics, Cell Nucleus immunology, Gene Expression Regulation genetics, Gene Expression Regulation immunology, Humans, Intracellular Signaling Peptides and Proteins, Molecular Chaperones, Multiprotein Complexes genetics, Multiprotein Complexes immunology, Protein Kinases genetics, Protein Kinases immunology, Protein Phosphatase 2 genetics, Protein Phosphatase 2 immunology, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt immunology, Proto-Oncogene Proteins c-akt metabolism, Ribosomal Protein S6 Kinases, 70-kDa genetics, Ribosomal Protein S6 Kinases, 70-kDa immunology, Ribosomal Protein S6 Kinases, 70-kDa metabolism, STAT1 Transcription Factor genetics, STAT1 Transcription Factor immunology, Saccharomyces cerevisiae genetics, Saccharomyces cerevisiae metabolism, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism, TOR Serine-Threonine Kinases, Cell Nucleus metabolism, Multiprotein Complexes metabolism, Protein Kinases metabolism, Protein Phosphatase 2 metabolism, STAT1 Transcription Factor metabolism
- Abstract
Target of rapamycin (TOR) is a highly conserved serine/threonine kinase that controls cell growth, primarily via regulation of protein synthesis. In Saccharomyces cerevisiae, TOR can also suppress the transcription of stress response genes by a mechanism involving Tap42, a serine/threonine phosphatase subunit, and the transcription factor Msn2. A physical association between mammalian TOR (mTOR) and the transcription factor signal transducer and activator of transcription-1 (STAT1) was recently identified in human cells, suggesting a similar role for mTOR in the transcription of interferon-gamma-stimulated genes. In the current study, we identified a macromolecular protein complex composed of mTOR, STAT1, the Tap42 homologue alpha4, and the protein phosphatase 2A catalytic subunit (PP2Ac). Inactivation of mTOR enhanced its association with STAT1 and increased STAT1 nuclear content in PP2Ac-dependent fashion. Depletion of alpha4, PP2A, or mTOR enhanced the induction of early (i.e. IRF-1) and late (i.e. caspase-1, hiNOS, and Fas) STAT1-dependent genes. The regulation of IRF-1 or caspase-1 by mTOR was independent of other known mTOR effectors p70 S6 kinase and Akt. These results describe a new role for mTOR and alpha4/PP2A in the control of STAT1 nuclear content, and the expression of interferon-gamma-sensitive genes involved in immunity and apoptosis.
- Published
- 2009
- Full Text
- View/download PDF