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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adaptor Proteins, Signal Transducing / genetics
-
Adaptor Proteins, Signal Transducing / metabolism
-
Apoptosis / genetics
-
Apoptosis / immunology
-
Cell Line
-
Cell Nucleus / genetics
-
Cell Nucleus / immunology
-
Cell Nucleus / metabolism*
-
Gene Expression Regulation / genetics
-
Gene Expression Regulation / immunology
-
Humans
-
Intracellular Signaling Peptides and Proteins
-
Molecular Chaperones
-
Multiprotein Complexes / genetics
-
Multiprotein Complexes / immunology
-
Multiprotein Complexes / metabolism*
-
Protein Kinases / genetics
-
Protein Kinases / immunology
-
Protein Kinases / metabolism*
-
Protein Phosphatase 2 / genetics
-
Protein Phosphatase 2 / immunology
-
Protein Phosphatase 2 / metabolism*
-
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
-
STAT1 Transcription Factor / metabolism*
-
Saccharomyces cerevisiae / genetics
-
Saccharomyces cerevisiae / metabolism
-
Saccharomyces cerevisiae Proteins / genetics
-
Saccharomyces cerevisiae Proteins / metabolism
-
TOR Serine-Threonine Kinases
Substances
-
Adaptor Proteins, Signal Transducing
-
IGBP1 protein, human
-
Intracellular Signaling Peptides and Proteins
-
Molecular Chaperones
-
Multiprotein Complexes
-
STAT1 Transcription Factor
-
STAT1 protein, human
-
Saccharomyces cerevisiae Proteins
-
TAP42 protein, S cerevisiae
-
Protein Kinases
-
MTOR protein, human
-
Proto-Oncogene Proteins c-akt
-
Ribosomal Protein S6 Kinases, 70-kDa
-
TOR Serine-Threonine Kinases
-
PPP2CA protein, human
-
Protein Phosphatase 2