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HIF-transcribed p53 chaperones HIF-1α

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 ha...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821315/
https://www.ncbi.nlm.nih.gov/pubmed/31538203
http://dx.doi.org/10.1093/nar/gkz766
Descripción
Sumario: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.