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Regulation of karyopherin alpha1 and nuclear import by mammalian target of rapamycin

Item Type:Article
Title:Regulation of karyopherin alpha1 and nuclear import by mammalian target of rapamycin
Creators Name:Fielhaber, J.A. and Tan, J. and Joung, K.B. and Attias, O. and Huegel, S. and Bader, M. and Roux, P.P. and Kristof, A.S.
Abstract:Under conditions of reduced mitogen or nutritional substrate levels, the serine/threonine kinase target of rapamycin (TOR) 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 signal transducer and activator of transcription-1 (STAT1) regulates a subset of genes involved in immune modulation and apoptosis. Based on previous work indicating a functional relationship between mTOR and the nuclear content of latent STAT1, we investigate the mechanism by which mTOR controls STAT1 nuclear import. By fluorescence confocal microscopy, inactivation of mTOR with rapamycin promoted the nuclear translocation of unphosphorylated STAT1, but not that of a STAT1 mutant incapable of binding its nuclear import adaptor karyopherin-alpha1 (KPNA1). By immunoprecipitation, KPNA1 was physically associated with mTOR and STAT1 in a complex that translocated to the nucleus in response to rapamycin. Although mTOR was not a kinase for KPNA1, the mTOR-associated phosphatase protein phosphatase 2A catalytic (PP2Ac) interacted directly with KPNA1, and regulated nuclear import of the mTOR/KPNA1 complex. KPNA1, or its interaction with STAT, 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, mTOR and PP2Ac control the constitutive nuclear import of latent STAT1 by KPNA1, which are key modulators of STAT1 expression and apoptosis.
Keywords:Gene Expression, mTOR, Nuclear Transport, Protein Phosphatase, STAT Transcription Factor, Importin, Karyopherin, Animals, Mice
Source:Journal of Biological Chemistry
Publisher:American Society for Biochemistry and Molecular Biology
Page Range:14325-14335
Date:27 April 2012
Official Publication:https://doi.org/10.1074/jbc.M111.246785
PubMed:View item in PubMed

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