Phosphorylation of 4E-BP1 is mediated by the p38/MSK1 pathway in response to UVB irradiation.
In resting cells, eIF4E-binding protein 1 (4E-BP1) binds to the eukaryotic initiation factor-4E (eIF-4E), preventing formation of a functional eIF-4F complex essential for cap-dependent initiation of translation. Phosphorylation of 4E-BP1 dissociates it from eIF-4E, relieving the translation block. Studies suggested that insulin- or growth factor-induced 4E-BP1 phosphorylation is mediated by phosphatidylinositol 3-kinase (PI3-kinase) and its downstream protein kinase, Akt. In the present study we demonstrated that UVB induced 4E-BP1 phosphorylation at multiple sites, Thr-36, Thr-45, Ser-64, and Thr-69, leading to dissociation of 4E-BP1 from eIF-4E. UVB-induced phosphorylation of 4E-BP1 was blocked by p38 kinase inhibitors, PD169316 and SB202190, and MSK1 inhibitor, H89, but not by mitogen-activated protein kinase kinase inhibitors, PD98059 or U0126. The PI3-kinase inhibitor, wortmannin, did not block UVB-induced 4E-BP1 phosphorylation, but blocked both UVB- and insulin-induced activation of PI3-kinase and phosphorylation of Akt. 4E-BP1 phosphorylation was blocked in JB6 Cl 41 cells expressing a dominant negative p38 kinase or dominant negative MSK1, but not in cells expressing dominant negative ERK2, JNK1, or PI3-kinase p85 subunit. Our results suggest that UVB induces phosphorylation of 4E-BP1, leading to the functional dissociation of 4E-BP1 from eIF-4E. The p38/MSK1 pathway, but not PI3-kinase or Akt, is required for mediating the UVB-induced 4E-BP1 phosphorylation.
Liu
Guangming
G
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Zhang
Yiguo
Y
Bode
Ann M
AM
Ma
Wei-Ya
WY
Dong
Zigang
Z
D000730:Androstadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism / Q000528:radiation effects*; D039561:Eukaryotic Initiation Factor-4E; D005419:Flavonoids / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010448:Peptide Initiation Factors / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism / Q000528:radiation effects*; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D019893:Ribosomal Protein S6 Kinases / Q000502:physiology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D020123:Sirolimus / Q000494:pharmacology; D013449:Sulfonamides; D014466:Ultraviolet Rays; D000077191:Wortmannin; D048051:p38 Mitogen-Activated Protein Kinases
D000730:Androstadienes; D002352:Carrier Proteins; D039561:Eukaryotic Initiation Factor-4E; D005419:Flavonoids; D007093:Imidazoles; D007546:Isoquinolines; D010448:Peptide Initiation Factors; D010750:Phosphoproteins; D011725:Pyridines; D013449:Sulfonamides; D019869:Phosphatidylinositol 3-Kinases; D019893:Ribosomal Protein S6 Kinases; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C408604:2-(4-nitrophenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazole; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus; D000077191:Wortmannin