Regulation of translation factors eIF4GI and 4E-BP1 during recovery of protein synthesis from inhibition by p53.
Activation of the tumour suppressor protein p53 rapidly inhibits protein synthesis. This is associated with dephosphorylation and cleavage of initiation factor eIF4GI and the eIF4E-binding protein 4E-BP1. When the activation of p53 is reversed within 16 h 4E-BP1 becomes rephosphorylated, the level of intact eIF4GI slowly increases and protein synthesis gradually recovers. The recovery of protein synthesis is partially blocked by rapamycin and wortmannin but not by the protein kinase inhibitors PD98059 and CGP74514A. Both rapamycin and wortmannin, but not PD98059 or CGP74514A, delay the reappearance of eIF4GI. In contrast, full-length 4E-BP1 rapidly becomes rephosphorylated and this process is partially inhibited by rapamycin, PD98059 and CGP74514A. Thus, activation of p53 results in the inhibition of distinct rapamycin- and wortmannin-sensitive pathways that target eIF4GI, and rapamycin-sensitive and -insensitive pathways that target 4E-BP1. Following inactivation of p53 the gradual recovery is determined largely by the kinetics of restoration of eIF4GI rather than by the rephosphorylation of full-length 4E-BP1. These findings suggest that the ability of cells to rephosphorylate 4E-BP1, resynthesise eIF4GI and restore the rate of protein synthesis after inactivation of p53 is an important aspect of recovery following the relief of physiological stress.
Constantinou
C
C
Translational Control Group, Centre for Molecular and Metabolic Signalling, Division of Basic Medical Sciences, St George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
Clemens
M J
MJ
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins; D016923:Cell Death; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors; D005786:Gene Expression Regulation; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D014176:Protein Biosynthesis; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D013696:Temperature; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism* / Q000502:physiology; D000077191:Wortmannin
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C113920:EIF4G1 protein, human; C499527:Eif4ebp1 protein, mouse; C491908:Eif4g1 protein, mouse; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D010446:Peptide Fragments; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D016159:Tumor Suppressor Protein p53; D020123:Sirolimus; D000077191:Wortmannin