title: p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2.
abstract: In cancer cells, the aberrant conversion of pyruvate into lactate instead of acetyl-CoA in the presence of oxygen is known as the Warburg effect. The consequences and mechanisms of this metabolic peculiarity are incompletely understood. Here we report that p53 status is a key determinant of the Warburg effect. Wild-type p53 expression decreased levels of pyruvate dehydrogenase kinase-2 (Pdk2) and the product of its activity, the inactive form of the pyruvate dehydrogenase complex (P-Pdc), both of which are key regulators of pyruvate metabolism. Decreased levels of Pdk2 and P-Pdc in turn promoted conversion of pyruvate into acetyl-CoA instead of lactate. Thus, wild-type p53 limited lactate production in cancer cells unless Pdk2 could be elevated. Together, our results established that wild-type p53 prevents manifestation of the Warburg effect by controlling Pdk2. These findings elucidate a new mechanism by which p53 suppresses tumorigenesis acting at the level of cancer cell metabolism.
authors: Raymond and Beverly Sackler Foundation, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey, USA.
authors: Tanupriya
authors: T
authors: Contractor
authors: Chris R
authors: CR
authors: Harris
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D016158:Genes, p53; D045325:HCT116 Cells; D006801:Humans; D007773:Lactates / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D014158:Transcription, Genetic; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D007773:Lactates; C000631430:PDK2 protein, human; C000631435:Pdk2 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D017346:Protein Serine-Threonine Kinases