Reports

S6K1- and ßTRCP-Mediated Degradation of PDCD4 Promotes Protein Translation and Cell Growth

N. Valerio Dorrello,^1* Angelo Peschiaroli,^1* Daniele Guardavaccaro,¹ Nancy H. Colburn,² Nicholas E. Sherman,³ Michele Pagano¹

The tumor suppressor programmed cell death protein 4 (PDCD4) inhibits the translation initiation factor eIF4A, an RNA helicase that catalyzes the unwinding of secondary structure at the 5' untranslated region (5'UTR) of messenger RNAs (mRNAs). In response to mitogens, PDCD4 was rapidly phosphorylated on Ser⁶⁷ by the protein kinase S6K1 and subsequently degraded via the ubiquitin ligase SCF^ßTRCP. Expression in cultured cells of a stable PDCD4 mutant that is unable to bind ßTRCP inhibited translation of an mRNA with a structured 5'UTR, resulted in smaller cell size, and slowed down cell cycle progression. We propose that regulated degradation of PDCD4 in response to mitogens allows efficient protein synthesis and consequently cell growth.

¹ Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
² Laboratory of Cancer Prevention, National Cancer Institute, Building 576, Frederick, MD 21702, USA.
³ W. M. Keck Biomedical Mass Spectrometry Lab, University of Virginia, Charlottesville, VA 22908, USA.

^* These authors contributed equally to this work.

To whom correspondence should be addressed. E-mail: michele.pagano{at}med.nyu.edu

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