PKB/Akt activation inhibits p53-mediated HIF1A degradation that is independent of MDM2

Cross‐talk between the two transcription factors, p53 and hypoxia inducible factor 1α (HIF1A), is important in different pathophysiological conditions (Hammond and Giaccia, 2006, Clin Cancer Res 12:5007–5009) such as in the transition from myocardial hypertrophy to cardiac dilatation and heart failu...

Full description

Saved in:
Bibliographic Details
Published in:Journal of cellular physiology 2010-03, Vol.222 (3), p.635-639
Main Authors: Choy, Mun-Kit, Movassagh, Mehregan, Bennett, Martin R., Foo, Roger S.-Y.
Format: Article
Language:English
Subjects:
Animals
Cardiomegaly - enzymology
Cardiomegaly - pathology
Cell Line
Cell Size
Chromones - pharmacology
Deferoxamine - pharmacology
Disease Models, Animal
Fibroblasts - metabolism
Hypoxia-Inducible Factor 1, alpha Subunit - genetics
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Mice
Mice, Knockout
Morpholines - pharmacology
Myoblasts, Cardiac - drug effects
Myoblasts, Cardiac - enzymology
Myoblasts, Cardiac - pathology
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Proteasome Endopeptidase Complex - metabolism
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-akt - metabolism
Proto-Oncogene Proteins c-mdm2 - deficiency
Proto-Oncogene Proteins c-mdm2 - genetics
Proto-Oncogene Proteins c-mdm2 - metabolism
Rats
RNA, Messenger - metabolism
Serine
Time Factors
Transfection
Tumor Suppressor Protein p53 - deficiency
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Ubiquitination
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cross‐talk between the two transcription factors, p53 and hypoxia inducible factor 1α (HIF1A), is important in different pathophysiological conditions (Hammond and Giaccia, 2006, Clin Cancer Res 12:5007–5009) such as in the transition from myocardial hypertrophy to cardiac dilatation and heart failure. In that context, p53 induces HIF1A degradation which in turn provokes the transition from compensatory hypertrophy to myocardial thinning and chamber dilatation (Sano et al., 2007, Nature 446:444–448). In order to investigate the mechanism of p53‐induced HIF1A degradation, we used the established in vitro model of deferroxamine (DFX)‐induced HIF1A accumulation in H9c2 cardiac cells (Sano et al., 2007, Nature 446:444–448). Here, we report that opposite to HIF1A accumulation following exposure to DFX, prolonged DFX‐induced p53 activation and HIF1A protein decrease, without any change in Hif1a mRNA. HIF1A protein decrease accompanied upregulated HIF1A ubiquitination. MDM2, an ubiquitin E3 ligase target gene of p53, was upregulated following prolonged DFX, but using p53/Mdm2 double‐null mouse embryonic fibroblasts, we found that p53 upregulated HIF1A ubiquitination and degradation independently of MDM2. Moreover, with prolonged DFX treatment, an enhanced interaction between MDM2 and HIF1A was lacking. Instead, phospho‐Aktser473 was decreased during the phase coinciding with HIF1A degradation, and inhibition of PKB/Akt phosphorylation using PI3K inhibitor (LY294002) upregulated HIF1A ubiquitination. In summary, we propose that p53‐induced HIF1A degradation is not exclusively MDM2‐mediated, but reversible by PKB/Akt phosphorylation. J. Cell. Physiol. 222: 635–639, 2010. © 2009 Wiley‐Liss, Inc.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.21980