HIF-1 (hypoxia-inducible factor-1), a heterodimeric transcription factor comprising HIF-1α and HIF-1β subunits, serves as a key regulator of metabolic adaptation to hypoxia. HIF-1 activity largely increases during hypoxia by attenuating pVHL (von Hippel–Lindau protein)-dependent ubiquitination and subsequent 26 S-proteasomal degradation of HIF-1α. Besides HIF-1, the transcription factor and tumour suppressor p53 accumulates and is activated under conditions of prolonged/severe hypoxia. Recently, the interaction between p53 and HIF-1α was reported to evoke HIF-1α degradation. Destruction of HIF-1α by p53 was corroborated in the present study by using pVHL-deficient RCC4 (renal carcinoma) cells, supporting the notion of a pVHL-independent degradation process. In addition, low p53 expression repressed HIF-1 transactivation without affecting HIF-1α protein amount. Establishing that p53-evoked inhibition of HIF-1 reporter activity was relieved upon co-transfection of p300 suggested competition between p53 and HIF-1 for limiting amounts of the shared co-activator p300. This assumption was confirmed by showing competitive binding of in vitro transcription/translation-generated p53 and HIF-1α to the CH1 domain of p300 in vitro. We conclude that low p53 expression attenuates HIF-1 transactivation by competing for p300, whereas high p53 expression destroys the HIF-1α protein and thereby eliminates HIF-1 reporter activity. Thus once p53 becomes activated under conditions of severe hypoxia/anoxia, it contributes to terminating HIF-1 responses.
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Research Article| May 15 2004
p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1)
Bernhard BRÜNE 1
Department of Cell Biology, Faculty of Biology, University of Kaiserslautern, Erwin Schroedinger Strasse 13/4, 67663 Kaiserslautern, Germany
1To whom correspondence should be addressed (e-mail email@example.com).
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Tobias SCHMID, Jie ZHOU, Roman KÖHL, Bernhard BRÜNE; p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J 15 May 2004; 380 (1): 289–295. doi: https://doi.org/10.1042/bj20031299
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