MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner

Jul 2, 2014The Journal of biological chemistry

MDM2 controls the stability of low-oxygen sensing protein HIF-1α through protein breakdown and cell growth pathways involving PTEN and PI3K-AKT

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

PTEN inhibition reduces HIF1α accumulation under hypoxic conditions.

HIF1α, a protein that regulates gene expression during low oxygen levels, accumulates due to decreased degradation.
PTEN specifically inhibits the accumulation of HIF1α in response to hypoxia in genetically engineered cell lines.
In glioblastoma cell lines, blocking the PI3K pathway with specific inhibitors prevents the induction of HIF1α and its target genes.
HIF1α can be degraded via the 26 S proteasome under hypoxic conditions, with MDM2 acting as the E3 ligase responsible for this degradation.
The regulation of HIF1α degradation under hypoxia is influenced by the PTEN-PI3K-AKT signaling pathway.

AI simplified

Hypoxia-inducible factor 1 (HIF1) is a heterodimeric transcription factor containing an inducibly expressed HIF1α subunit and a constitutively expressed HIF1β subunit. Under hypoxic conditions, the HIF1α subunit accumulates because of a decrease in the rate of proteolytic degradation, and the resulting HIF1α-HIF1β heterodimers undergo post-translational modifications that promote transactivation. Previous reports suggest that amplified signaling through PI3K enhances HIF1-dependent gene expression; however, its role is controversial, and the mechanism is unclear. Using genetically engineered PTEN-deficient cell lines, we demonstrate that PTEN specifically inhibited the accumulation of HIF1α in response to hypoxia. Furthermore, we report that in glioblastoma cell lines, inhibition of PI3K pathway, using pan as well as isoform-specific PI3K inhibitors SF1126, PF4691502, BEZ-235, GDC0941, and TGX221 blocked the induction of HIF1α protein and its targets vascular endothelial growth factor, HK1, and GLUT1 mRNA in response to hypoxia. Herein, we describe the first evidence that HIF1α can be degraded under hypoxic conditions via the 26 S proteasome and that MDM2 is the E3 ligase that induces the hypoxic degradation of HIF1α. Moreover, the action of MDM2 on HIF1α under hypoxia occurs in the cytoplasm and is controlled by the PTEN-PI3K-AKT signaling axis. These data strongly suggest a new role for PTEN in the regulation of HIF1α and importantly that PI3K-AKT activation is required for the hypoxic stabilization of HIF1α and that hypoxia alone is not sufficient to render HIF1α resistant to proteasomal cleavage and degradation. Moreover, these findings suggest new therapeutic considerations for PI3K and/or AKT inhibitors for cancer therapeutics.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

MDM2 Regulates Hypoxic Hypoxia-inducible Factor 1α Stability in an E3 Ligase, Proteasome, and PTEN-Phosphatidylinositol 3-Kinase-AKT-dependent Manner

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief