S6K1- and ßTrcp-mediated
degradation of PDCD4 promotes protein translation and cell growth.
N. V. Dorrello, A. Peschiaroli, D. Guardavaccaro, N. Colburn, N. Sherman
and M. Pagano.
Science,
314:467-471, 2006.
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(betaTRCP). Expression in cultured cells of a stable
PDCD4 mutant that is unable to bind betaTRCP 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.
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