HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 20, 20950-20958, May 14, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/20/20950    most recent M312401200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Goruppi, S. Articles by Kyriakis, J. M. Search for Related Content PubMed PubMed Citation Articles by Goruppi, S. Articles by Kyriakis, J. M. Social Bookmarking                      What's this?

The Pro-hypertrophic Basic Helix-Loop-Helix Protein p8 Is Degraded by the Ubiquitin/Proteasome System in a Protein Kinase B/Akt- and Glycogen Synthase Kinase-3-dependent Manner, whereas Endothelin Induction of p8 mRNA and Renal Mesangial Cell Hypertrophy Require NFAT4^*

Sandro Goruppi and John M. Kyriakis

From the Molecular Cardiology Research Institute, Tufts-New England Medical Center and the Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts 02111

Renal disease is a common complication of diabetes. The initiating events in diabetic nephropathy are triggered by hyperglycemia and, possibly, advanced glycation end products. Subsequently, excess levels of vasoactive peptides (especially endothelin-1 (ET-1)) accumulate in the diabetic kidney, and there is evidence that these peptides mediate many of the pathophysiological changes associated with diabetic renal disease. These changes include an excess deposition of extracellular matrix proteins into the glomerular basement membrane and renal mesangial cell hypertrophy. Our transcriptional profiling studies have revealed that the p8 gene, which encodes a putative basic helix-loop-helix protein, is strongly induced in ET-1-treated renal mesangial cells and in an animal model of diabetic nephropathy. RNA interference experiments indicated that the p8 gene is required for ET-1-induced mesangial cell hypertrophy. Here, we show that the p8 polypeptide is a phosphoprotein subject to constitutive degradation by the ubiquitin/proteasome system. This degradation is mediated by phosphatidylinositol 3-kinase and protein kinase B/Akt. By contrast, stabilization of the p8 protein requires glycogen synthase kinase-3. Finally, short interfering RNA-mediated RNA interference experiments indicated that ET-1-stimulated mesangial cell hypertrophy and p8 mRNA induction require the NFAT4 transcription factor. Thus, p8 levels in the cell are likely maintained by a balance between signal-dependent transcriptional induction and proteolysis.

Received for publication, November 12, 2003 , and in revised form, March 4, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Molecular Cardiology Research Inst., Tufts-New England Medical Center, 750 Washington St., P. O. Box 8486, Boston, MA 02111. Tel.: 617-636-5190; Fax: 617-636-5204; E-mail: jkyriakis{at}tufts-nemc.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. Goruppi, R. D. Patten, T. Force, and J. M. Kyriakis Helix-Loop-Helix Protein p8, a Transcriptional Regulator Required for Cardiomyocyte Hypertrophy and Cardiac Fibroblast Matrix Metalloprotease Induction Mol. Cell. Biol., February 1, 2007; 27(3): 993 - 1006. [Abstract] [Full Text] [PDF]

				G. Path, A. Opel, M. Gehlen, V. Rothhammer, X. Niu, C. Limbert, L. Romfeld, S. Hugl, A. Knoll, M. D. Brendel, et al. Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1168 - E1176. [Abstract] [Full Text] [PDF]

				C. V. Garat, D. Fankell, P. F. Erickson, J. E.-B. Reusch, N. N. Bauer, I. F. McMurtry, and D. J. Klemm Platelet-Derived Growth Factor BB Induces Nuclear Export and Proteasomal Degradation of CREB via Phosphatidylinositol 3-Kinase/Akt Signaling in Pulmonary Artery Smooth Muscle Cells. Mol. Cell. Biol., July 1, 2006; 26(13): 4934 - 4948. [Abstract] [Full Text] [PDF]