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Articles in PresS, published online ahead of print August 13, 2002
Am J Physiol Renal Physiol, 10.1152/ajprenal.00109.2002
Submitted on March 21, 2002
Accepted on July 28, 2002
1 Division of Nephrology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
2 Geriatrics Research and Education Center, San Antonio, Texas, USA
3 Department of Biochemistry, McGill University, Montreal, Canada
* To whom correspondence should be addressed. E-mail: kasinath{at}uthscsa.edu.
Protein synthesis is required for renal hypertrophy and proximal tubular epithelial (named MCT) cells are an important cell-type involved in this process. We examined IGF-I regulation of protein synthesis in MCT cells. We focused on initial events in protein translation and the signaling events involved. Translation of capped mRNAs is under the control of eukaryotic initiation factor 4E (eIF4E). In the resting cell, eIF4E is normally kept in an inactive state by binding to 4E-BP1, its binding protein. Phosphorylation of 4E-BP1 results in dissociation of the eIF4E-4E-BP1 complex allowing eIF4E to initiate peptide synthesis. IGF-I stimulated protein synthesis, augmented phosphorylation of 4E-BP1, and promoted the dissociation of eIF4E from 4E-BP1. IGF-I stimulated the activities of PI 3-kinase, Akt and Erk-1/-2 type MAP kinase in MCT cells. IGF-I-induced phosphorylation of 4E-BP1, dissociation of the 4E-BP1-eIF4E complex, and increase in protein synthesis required activation of both PI 3-kinase and Erk pathways. Furthermore, Erk activation by IGF-I was also PI 3-kinase dependent. Transfection with Thr37,46
Ala37,46 mutant of 4E-BP1 showed that phosphorylation of Thr37,46 residues was required for IGF-I-induction of protein synthesis in MCT cells. Our observations reveal the importance of initial events in protein translation in IGF-I-induced protein synthesis in MCT cells, and identify regulatory signaling pathways involved.
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