Regulation of Karyopherin α1 and Nuclear Import by Mammalian Target of Rapamycin

Fielhaber, Jill A.; Tan, Jason; Joung, Kwang-Bo; Attias, Ortal; Huegel, Stefanie; Bäder, Michael; Roux, Philippe P.; Kristof, Arnold S.

doi:10.1074/jbc.m111.246785

Cited by 15 publications

(22 citation statements)

References 42 publications

(63 reference statements)

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“…Caspase-3 (CASP3) cleavage products were measured as a marker of apoptosis. As previously shown (20), cleaved CASP3 levels were reduced in STAT1-deficient U3A cells compared with those in 2fTGH controls (Fig. 4A, columns 5 versus 1); rapamycin significantly increased cleaved CASP3 levels in 2fTGH but not in U3A cells (Fig.…”

Section: Versus 3)supporting

confidence: 80%

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Regulation of ULK1 Expression and Autophagy by STAT1

Goldberg

Nkengfac

Sanchez

et al. 2017

Journal of Biological Chemistry

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Autophagy involves the lysosomal degradation of cytoplasmic contents for regeneration of anabolic substrates during nutritional or inflammatory stress. Its initiation occurs rapidly after inactivation of the protein kinase mammalian target of rapamycin (mTOR) (or mechanistic target of rapamycin), leading to dephosphorylation of Unc-51-like kinase 1 (ULK1) and autophagosome formation. Recent studies indicate that mTOR can, in parallel, regulate the activity of stress transcription factors, including signal transducer and activator of transcription-1 (STAT1). The current study addresses the role of STAT1 as a transcriptional suppressor of autophagy genes and autophagic activity. We show that STAT1-deficient human fibrosarcoma cells exhibited enhanced autophagic flux as well as its induction by pharmacological inhibition of mTOR. Consistent with enhanced autophagy initiation, ULK1 mRNA and protein levels were increased in STAT1-deficient cells. By chromatin immunoprecipitation, STAT1 bound a putative regulatory sequence in the ULK1 5'-flanking region, the mutation of which increased ULK1 promoter activity, and rendered it unresponsive to mTOR inhibition. Consistent with an anti-apoptotic effect of autophagy, rapamycin-induced apoptosis and cytotoxicity were blocked in STAT1-deficient cells but restored in cells simultaneously exposed to the autophagy inhibitor ammonium chloride. In vivo, skeletal muscle ULK1 mRNA and protein levels as well as autophagic flux were significantly enhanced in STAT1-deficient mice. These results demonstrate a novel mechanism by which STAT1 negatively regulates ULK1 expression and autophagy.

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Section: Versus 3)supporting

confidence: 80%

“…When inactivated, mTORC1 associates with latent (i.e. unphosphorylated) STAT1 in a macromolecular complex (18), enhances its nuclear import (20), and augments the subsequent induction of STAT1-dependent apoptosis genes. Mechanisms of latent STAT1 signaling and its regulation of apoptosis genes are reviewed in Yang and Stark (42).…”

Section: Discussionmentioning

confidence: 99%

Regulation of ULK1 Expression and Autophagy by STAT1

Goldberg

Nkengfac

Sanchez

et al. 2017

Journal of Biological Chemistry

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“…In addition, the rapamycin-induced KPNA2 decrease was abolished in the presence of the proteasome inhibitor MG132 (Figure 3B ), suggesting that the mTOR pathway modulated the proteasome-mediated KPNA2 degradation in NSCLC cells. Notably, previous studies have shown that KPNA1 (a STAT1 karyopherin) interacts with mTORC1 in a complex that includes STAT1 and the mTOR-associated phosphatase PP2Ac [ 29 ]. To investigate whether mTOR modulated KPNA2 degradation through a physical association with KPNA2, we determined the association between KPNA2 and phospho-mTOR/mTOR by an immunoprecipitation assay.…”

Section: Resultsmentioning

confidence: 99%

mTOR regulates proteasomal degradation and Dp1/E2F1- mediated transcription of KPNA2 in lung cancer cells

et al. 2016

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Karyopherin subunit alpha-2 (KPNA2) is overexpressed in various human cancers and is associated with cancer invasiveness and poor prognosis in patient. Nevertheless, the regulation of KPNA2 expression in cancers remains unclear. We herein applied epidermal growth factor (EGF) and five EGF receptor (EGFR)-related kinase inhibitors to investigate the role of EGFR signaling in KPNA2 expression in non-small cell lung cancer (NSCLC) cells. We found that EGFR signaling, particularly the mammalian target of rapamycin (mTOR) activity was positively correlated with KPNA2 protein levels in NSCLC cells. The mTOR inhibitors and mTOR knockdown reduced the protein and mRNA levels of KPNA2 in NSCLC and breast cancer cells. Specifically, rapamycin treatment induced proteasome-mediated KPNA2 protein decay and attenuated the transcriptional activation of KPNA2 by decreasing Dp1/E2F1 level in vivo. Immunoprecipitation assay further revealed that KPNA2 physically associated with the phospho-mTOR/mTOR and this association was abolished by rapamycin treatment. Collectively, our results show for the first time that KPNA2 is transcriptionally and post-translationally regulated by the mTOR pathway and provide new insights into targeted therapy for NSCLC.

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“…Zhao et al () found that autophagy activity was markedly increased when glioma stem/progenitor cells (GSPCs) were induced to differentiate using fetal calf serum (FCS), and that rapamycin, the activator of autophagy, could promote their differentiation. The mTOR signaling pathway was involved the regulation of autophagy, and mTOR could turn into its activated form, phospho‐mTOR, which can respond directly to mTOR activity (Fielhaber et al, ). Our study demonstrated that the expression of p‐mTOR, p‐p70S6K, and p‐4E‐BP1 declined after induction compared, which indicates that mTOR activity decreased during the neuronal differentiation.…”

Section: Discussionmentioning

confidence: 99%

Role of autophagy and mTOR signaling in neural differentiation of bone marrow mesenchymal stem cells

Wang

Zhang

et al. 2014

Cell Biology International

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Autophagy is involved in cell differentiation. We present evidence that autophagy is activated during β-mercaptoethanol (β-ME)-induced neuronal differentiation of bone marrow mesenchymal stem cells (MSCs), in which mammalian target of rapamycin (mTOR) signaling is important. mTOR activity declined after being transported from the nucleus to the cytoplasm. Using 3-methyladenine (3-MA) and rapamycin to regulate the activity of mTOR, it was found that the efficiency of neuronal differentiation was affected.

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Regulation of Karyopherin α1 and Nuclear Import by Mammalian Target of Rapamycin

Cited by 15 publications

References 42 publications

Regulation of ULK1 Expression and Autophagy by STAT1

Regulation of ULK1 Expression and Autophagy by STAT1

mTOR regulates proteasomal degradation and Dp1/E2F1- mediated transcription of KPNA2 in lung cancer cells

Role of autophagy and mTOR signaling in neural differentiation of bone marrow mesenchymal stem cells

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