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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Thiaville, Michelle M. Gjymishka, Altin Kilberg, Michael S. Kaufman, Randal J. Pan, Yuan-xiang Zhong, Can |
| Description | Author Affiliation: Thiaville MM ( Department of Biochemistry and Molecular Biology, Genetics Institute, Shands Cancer Center and Center for Nutritional Sciences, University of Florida College of Medicine, Gainesville, Florida 32610, USA.) |
| Abstract | The mammalian amino acid response (AAR) pathway is up-regulated by protein or amino acid depletion. This pathway involves detection of uncharged tRNA by the GCN2 kinase, phosphorylation of the translation initiation factor eIF2alpha (eukaryotic initiation factor 2alpha), and, through subsequent translational control, enhanced de novo synthesis of the transcription factor ATF4. The present studies demonstrate that inhibition of MEK activation in HepG2 human hepatoma cells by PD98059 or U0126 blocked the increased phosphorylation of eIF2alpha and ATF4 synthesis triggered by amino acid limitation, showing that the AAR requires activation of the MEK-ERK pathway. Inhibitors of the JNK or p38 MAPK pathways were ineffective. Consequently, inhibition of MEK activation blocked transcriptional induction of ATF4 target genes, but the induction was rescued by overexpression of ATF4 protein. Furthermore, the enhanced ERK phosphorylation following amino acid deprivation required GCN2 kinase activity and eIF2alpha phosphorylation. Inhibition of protein phosphatase 1 action on phospho-eIF2alpha by knockdown of GADD34 did not block the sensitivity to PD98059, suggesting that MEK functions to enhance GCN2-dependent eIF2alpha phosphorylation rather than suppressing dephosphorylation. Collectively, these results document a critical interdependence between the MEK-ERK MAPK signaling pathway and the amino acid stress-activated pathway. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 16 |
| Volume Number | 283 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2008-04-18 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Eukaryotic Initiation Factor-2 Metabolism Mitogen-Activated Protein Kinase Kinases Protein-Serine-Threonine Kinases Physiology Animals Antigens, Differentiation Cell Cycle Proteins Cell Line Enzyme Inhibitors Pharmacology Flavonoids Mice Models, Biological Phosphorylation Protein Biosynthesis Protein Phosphatase 1 RNA, Small Interfering Signal Transduction Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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