HIF-transcribed p53 chaperones HIF-1α

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.

Oxygen-responsive p53 tetramer-octamer switch controls cell fate

“…S3D). FRET on beads assay results is in agreement with the recent finding that p53 interacts with HIF-1 complex upon chromatin for adaptive responses in hypoxia (30). Next, the complex was checked against anti-p53, anti-HIF-1α, and anti-HIF-1β antibodies by two different modes in order to identify homo-oligomeric state of p53 that associates with the HIF-1.…”

“…On the other hand, D⇀T can promote T-HIF-1 complex which displays a chaperone function of p53. Recently, it has been shown that WT and MT p53 binds to HIF-1 complex at chromatin for its stabilization upon HRE in controlling angiogenesis and other HIF-1α induced transformations in hypoxic tumor progression (30). Our three chromophore FRET setup identifies a distal and proximal arrangement of two HIF-1 subunits, α and β in hypoxia and normoxia by the presence of p53 respectively.…”

Metabolic Heterogeneity of Cancer Cells: An Interplay between HIF-1, GLUTs, and AMPK

“…With the use of the tumor metabolism modeling approach, it has been shown that in the hypoxic microenvironment, both intracellular and environmental factors contribute to metabolic reprogramming of cancer cells, and that various growth factor-initiated cell signaling cascades and transcription factors can affect HIF-1 activity [39]. An interplay between HIF-1 and a variety of oncogenes such as Ras, c-Myc, p53, AMPK, along with PKB/Akt, PI3K, and mTOR signaling pathways has been observed to control mitochondrial ETC functioning and energy production to maintain cancer cell proliferation and survival [40][41][42][43][44][45][46][47].…”

Hypoxia-Inducible Factor Is Critical for Pathogenesis and Regulation of Immune Cell Functions in Rheumatoid Arthritis

“…HIF is a heterodimeric complex, consisting of α subunits (HIF-1α, HIF-2α, or HIF-3α) and a β subunit (also known as aryl hydrocarbon receptor nuclear translocator or ARNT). Expression of the α subunit is regulated by oxygen concentration in the cytoplasm, while the β subunit is constitutively expressed in the cell nucleus (7,8). Both α and β subunits, which contain a basic helix-loop-helix (bHLH) domain and a PAS-A and PAS-B (Per, Arnt, and Sim; PAS) domain, could combine as a heterodimeric complex to bind to the hypoxia response element (HRE) within specific sequences of the promotors of target genes.…”