HIF-transcribed p53 chaperones HIF-1α

• Published in: Nucleic acids research Vol. 47; no. 19; pp. 10212 - 10234
• Main 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 04.11.2019
• Subjects: Cell Hypoxia - genetics; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Molecular Biology; Molecular Chaperones - genetics; Promoter Regions, Genetic - genetics; Protein Interaction Maps - genetics; Response Elements - genetics; Signal Transduction - genetics; Tumor Suppressor Protein p53 - genetics
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkz766

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.