HIF-transcribed p53 chaperones HIF-1α. Issue 19 (20th September 2019)

• Record Type: Journal Article
• Authors: Madan, Esha; Parker, Taylor M; Pelham, Christopher J; Palma, Antonio M; Peixoto, Maria L; Nagane, Masaki; Chandaria, Aliya; Tomás, Ana R; Canas-Marques, Rita; Henriques, Vanessa; Galzerano, Antonio; Cabral-Teixeira, Joaquim; Selvendiran, Karuppaiyah; Kuppusamy, Periannan; Carvalho, Carlos; Beltran, Antonio; Moreno, Eduardo; Pati, Uttam K; Gogna, Rajan
• Is Part Of: Nucleic acids research. Volume 47:Issue 19(2019)
• Page Start: 10212
• Page End: 10234
• Publication Date: 2019-09-20
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gkz766
• Languages: English
• ISSNs: 0305-1048

Abstract

Abstract: Chronic hypoxia is associated with a variety of physiological conditions such as rheumatoid arthritis, ischemia/reperfusion injury, stroke, diabetic vasculopathy, epilepsy and cancer. At the molecular level, hypoxia manifests its effects via activation of HIF-dependent transcription. On the other hand, an important transcription factor p53, which controls a myriad of biological functions, is rendered transcriptionally inactive under hypoxic conditions. p53 and HIF-1α are known to share a mysterious relationship and play an ambiguous role in the regulation of hypoxia-induced cellular changes. Here we demonstrate a novel pathway where HIF-1α transcriptionally upregulates both WT and MT p53 by binding to five response elements in p53 promoter. In hypoxic cells, this HIF-1α-induced p53 is transcriptionally inefficient but is abundantly available for protein-protein interactions. Further, both WT and MT p53 proteins bind and chaperone HIF-1α to stabilize its binding at its downstream DNA response elements. This p53-induced chaperoning of HIF-1α increases synthesis of HIF-regulated genes and thus the efficiency of hypoxia-induced molecular changes. This basic biology finding has important implications not only in the design of anti-cancer strategies but also for other physiological conditions where hypoxia results in disease manifestation.