Regulation of the PDK4 isozyme by the Rb-E2F1 complex

Hsieh, M. C., Das, D., Sambandam, N., Zhang, M. Q., Nahle, Z. (October 2008) Regulation of the PDK4 isozyme by the Rb-E2F1 complex. J Biol Chem, 283 (41). pp. 27410-7.

URL: http://www.ncbi.nlm.nih.gov/pubmed/18667418
DOI: 10.1074/jbc.M802418200

Abstract

Loss of the transcription factor E2F1 elicits a complex metabolic phenotype in mice underscored by reduced adiposity and protection from high fat diet-induced diabetes. Here, we demonstrate that E2F1 directly regulates the gene encoding PDK4 (pyruvate dehydrogenase kinase 4), a key nutrient sensor and modulator of glucose homeostasis that is chronically elevated in obesity and diabetes and acutely induced under the metabolic stress of starvation or fasting. We show that loss of E2F1 in vivo blunts PDK4 expression and improves myocardial glucose oxidation. The absence of E2F1 also corresponds to lower blood glucose levels, improved plasma lipid profile, and increased sensitivity to insulin stimulation. Consistently, enforced E2F1 expression up-regulates PDK4 levels and suppresses glucose oxidation in C(2)C(12) myoblasts. Furthermore, inactivation of Rb, the repressor of E2F-dependent transcription, markedly induces PDK4 and triggers the enrichment of E2F1 occupancy onto the PDK4 promoter as detected by chromatin immunoprecipitation analysis. Two overlapping E2F binding sites were identified on this promoter. Transactivation assays later verified E2F1 responsiveness of this promoter element in C(2)C(12) myoblasts and IMR90 fibroblasts, an effect that was completely abrogated following mutation of the E2F sites. Taken together, our data illustrate how the E2F1 mitogen directly regulates PDK4 levels and influences cellular bioenergetics, namely mitochondrial glucose oxidation. These results are relevant to the pathophysiology of chronic diseases like obesity and diabetes, where PDK4 is dysregulated and could have implications pertinent to the etiology of tumor metabolism, especially in cancers with Rb pathway defects.

Item Type: Paper
Subjects: diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
diseases & disorders > nutritional and metabolic diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
diseases & disorders > nutritional and metabolic diseases > diabetes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > transcription factor
CSHL Authors:
Communities: CSHL labs > Zhang lab
Depositing User: Matt Covey
Date: 10 October 2008
Date Deposited: 25 Feb 2013 20:58
Last Modified: 25 Feb 2013 20:58
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27609

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