S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth.
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.
Dorrello
N Valerio
NV
Department of Pathology, NYU Cancer Institute, New York University School of Medicine, 550 First Avenue, MSB 599, New York, NY 10016, USA.
Peschiaroli
Angelo
A
Guardavaccaro
Daniele
D
Colburn
Nancy H
NH
Sherman
Nicholas E
NE
Pagano
Michele
M
D020121:5' Untranslated Regions; D020816:Amino Acid Motifs; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D048429:Cell Size; D039601:Eukaryotic Initiation Factor-4A / Q000037:antagonists & inhibitors / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D039642:Eukaryotic Initiation Factors / Q000378:metabolism; D006801:Humans; D008934:Mitogens / Q000494:pharmacology; D010766:Phosphorylation; D014176:Protein Biosynthesis; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D044967:Serum; D015398:Signal Transduction; D044844:beta-Transducin Repeat-Containing Proteins / Q000235:genetics / Q000378:metabolism*
D020121:5' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D008934:Mitogens; C114487:PDCD4 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D044844:beta-Transducin Repeat-Containing Proteins; D012694:Serine; D044843:SKP Cullin F-Box Protein Ligases; D019893:Ribosomal Protein S6 Kinases; D039601:Eukaryotic Initiation Factor-4A