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.

Abstract	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.
Authors	Sandro Goruppi, John M Kyriakis
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 279 Issue 20 Pg. 20950-8 (May 14 2004) ISSN: 0021-9258 [Print] United States
PMID	15016802 (Publication Type: Journal Article)
Chemical References	Basic Helix-Loop-Helix Transcription Factors DNA-Binding Proteins Endothelins Multienzyme Complexes NFATC Transcription Factors Neoplasm Proteins Nerve Tissue Proteins Nfatc4 protein, rat Nupr1 protein, rat Proto-Oncogene Proteins RNA, Messenger Recombinant Proteins Transcription Factors Ubiquitin Akt1 protein, rat Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt Glycogen Synthase Kinase 3 Cysteine Endopeptidases Proteasome Endopeptidase Complex
Topics	Animals Basic Helix-Loop-Helix Transcription Factors Cell Culture Techniques Cysteine Endopeptidases (metabolism) DNA-Binding Proteins (genetics, metabolism) Diabetic Nephropathies (genetics, physiopathology) Disease Models, Animal Endothelins (pharmacology) Gene Expression Regulation (drug effects) Glomerular Mesangium (drug effects, pathology, physiology) Glycogen Synthase Kinase 3 (metabolism) Helix-Loop-Helix Motifs (physiology) Multienzyme Complexes (metabolism) NFATC Transcription Factors Neoplasm Proteins Nerve Tissue Proteins (metabolism) Proteasome Endopeptidase Complex Protein Serine-Threonine Kinases (metabolism) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt RNA, Messenger (genetics) Rats Recombinant Proteins (metabolism) Transcription Factors (metabolism) Transcription, Genetic (drug effects) Ubiquitin (metabolism)

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