التفاصيل البيبلوغرافية
| العنوان: |
Regulation of Karyopherin α1 and Nuclear Import by Mammalian Target of Rapamycin. |
| المؤلفون: |
Fielhaber, Jill A.1, Tan, Jason1, Joung, Kwang-Bo1, Attias, Ortal1, Huegel, Stefanie2, Bader, Michael2, Roux, Philippe P.3, Kristof, Arnold S.1 arnold.kristof@mcgill.ca |
| المصدر: |
Journal of Biological Chemistry. 4/27/2012, Vol. 287 Issue 18, p14325-14335. 11p. |
| مصطلحات موضوعية: |
*KARYOPHERINS, *RAPAMYCIN, *KINASES, *APOPTOSIS, *TRANSCRIPTION factors, *IMMUNOREGULATION, *IMMUNOLOGY |
| مستخلص: |
Under conditions of reduced mitogen or nutritional substrate levels, the serine/threonine kinase target of rapamycin can augment the nuclear content of distinct transcription factors and promote the induction of stress response genes. In its latent (i.e., unphosphorylated) form, the transcription factor STAT1 regulates a subset of genes involved in immune modulation and apoptosis. Based on previous work indicating a functional relationship between mammalian target of rapamycin (mTOR) and the nuclear content of latent STAT1, we investigated the mechanism by which mTOR controls STAT1 nuclear import. By fluorescence confocal microscopy, inactivation ofmTORwith rapamycin promoted the nuclear translocation of unphosphorylated STAT1, but not that of a STAT1 mutant incapable of binding its nuclear import adaptor karyopherin-α1 (KPNA1). By immunoprecipitation, KPNA1was physically associated withmTORand STAT1in a complex that translocated to the nucleus in response to rapamycin. Although mTOR is not a kinase for KPNA1, the mTOR-associated phosphatase protein phosphatase 2A catalytic interacted directly with KPNA1 and regulated nuclear import of the mTOR-KPNA1 complex. KPNA1, or its interaction with STAT1, was required for the nuclear import of latent STAT1, transcriptional induction of the STAT1 gene, and caspase-3 activation under conditions of reduced mTOR activity (i.e. rapamycin, glucose starvation, serum withdrawal). Therefore, at low mitogen or nutrient levels,mTORand protein phosphatase 2A catalytically control the constitutive nuclear import of latent STAT1 by KPNA1, which are key modulators of STAT1 expression and apoptosis. [ABSTRACT FROM AUTHOR] |
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