S6K1 triggers betaTRCP-mediated degradation of the tumour suppressor PDCD4 to promote translation.
| Evidence tier | D Mechanistic / in vitro / review |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Mammalian cells |
| Journal | Science |
| Year | 2006 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.1130276 · PMID 17053147 |
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.
| Intervention | Biochemical/genetic (S6K1, βTRCP, PDCD4) |
| Target | S6K1 / PDCD4 / eIF4A |
| Model | Mammalian cells |
| Effect | S6K1 phosphorylates PDCD4 (Ser67) triggering βTRCP-mediated degradation → promotes translation and cell growth |