Hdm2 Recruits a Hypoxia-Sensitive Corepressor to Negatively Regulate p53-Dependent Transcription

Abstract

The transcription factor p53 lies at the center of a protein network that controls cell cycle progression and commitment to apoptosis [1]. p53 is inactive in proliferating cells, largely because of negative regulation by the Hdm2/Mdm2 oncoprotein, with which it physically associates. Release from this negative regulation is sufficient to activate p53 [2] and can be triggered in cells by multiple stimuli through diverse pathways [3–5]. This diversity is achieved in part because Hdm2 uses multiple mechanisms to inactivate p53; it targets p53 for ubiquitination and degradation by the proteosome [6–8], shuttles it out of the nucleus and into the cytoplasm [9, 10], prevents its interaction with transcriptional coactivators [11], and contains an intrinsic transcriptional repressor activity [12]. Here we show that Hdm2 can also repress p53 activity through the recruitment of a known transcriptional corepressor, hCtBP2 [13, 14]. This interaction, and consequent repression of p53-dependent transcription, is relieved under hypoxia or hypoxia-mimicking conditions that are known to increase levels of intracellular NADH. CtBP proteins can undergo an NADH-induced conformational change [15], which we show here results in a loss of their Hdm2 binding ability. This pathway represents a novel mechanism whereby p53 activity can be induced by cellular stress.