Yogev, O; Goldberg, R; Anzi, S; Yogev, O; Shaulian, E; (2010) Jun Proteins Are Starvation-Regulated Inhibitors of Autophagy. CANCER RES , 70 (6) 2318 - 2327. 10.1158/0008-5472.CAN-09-3408.
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The growing number of biological functions affected by autophagy ascribes a special significance to identification of factors regulating it. The activator protein-1 (AP-1) transcription factors are involved in most aspects of cellular proliferation, death, or survival, yet no information regarding their involvement in autophagy is available. Here, we show that the AP-1 proteins JunB and c-Jun, but not JunD, c-Fos, or Fra-1, inhibit autophagy. JunB inhibits autophagy induced by starvation, overexpression of a short form of ARF (smARF), a potent inducer of autophagy, or even after rapamycin treatment. In agreement, acute repression of JunB expression, by JunB knockdown, potently induces autophagy. As expected from autophagy-inhibiting proteins, Jun B and c-Jun expression is reduced by starvation. Decrease in JunB mRNA expression and post-transcriptional events downregulate JunB protein expression after starvation. The inhibition of autophagy by JunB is not mediated by mammalian target of rapamycin (mTOR) regulation, as it occurs also in the absence of mTOR activity, and autophagy induced by JunB knockdown is not correlated with changes in mTOR activity. Nevertheless, the transcriptional activities of c-Jun and JunB are required for autophagy inhibition, and JunB incapable of heterodimerizing is a less effective inhibitor of autophagy. Most importantly, inhibition of autophagy in starved HeLa cells by JunB enhances apoptotic cell death. We suggest that JunB and c-Jun are regulators of autophagy whose expression responds to autophagy-inducing signals. Cancer Res; 70(6); 2318-27. (C) 2010 AACR.
|Title:||Jun Proteins Are Starvation-Regulated Inhibitors of Autophagy|
|Keywords:||B-KINASE IKK, TUMOR-SUPPRESSOR, CELL-DEATH, APOPTOSIS, DEGRADATION, BECLIN-1, DISEASE, GENE, PROLIFERATION, PROGRESSION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Wolfson Institute and Cancer Institute Administration > Cancer Institute > Research Department of Cancer Biology|
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