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

Choy, Mun-Kit ORCID: https://orcid.org/0000-0003-3998-0774, Movassagh, Mehregan, Bennett, Martin R and Foo, Roger S-Y (2010) PKB/Akt activation inhibits p53-mediated HIF1A degradation that is independent of MDM2. Journal of Cellular Physiology, 222 (3). pp. 635-639. ISSN 0021-9541

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Abstract

Cross-talk between the two transcription factors, p53 and hypoxia inducible factor 1alpha (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-Akt(ser473) 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.

Item Type:	Article (Article)
Peer-reviewed:	Yes
Date Deposited:	04 Jun 2024 09:10
Publisher:	Wiley
Additional Information:	For copyright reasons, full-text access is not possible through this repository. Access via https://doi.org/10.1002/jcp.21980.
Divisions:	Faculties > Science and Engineering
Subject terms:	Cell Line, Fibroblasts, Myoblasts, Cardiac, Animals, Mice, Knockout, Mice, Rats, Cardiomegaly, Disease Models, Animal, Deferoxamine, Morpholines, Chromones, Proteasome Endopeptidase Complex, Serine, RNA, Messenger, Protein Kinase Inhibitors, Transfection, Cell Size, Phosphorylation, Time Factors, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-mdm2, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Animals, Cardiomegaly, Cell Line, Cell Size, Chromones, Deferoxamine, Disease Models, Animal, Fibroblasts, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Knockout, Morpholines, Myoblasts, Cardiac, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Proteasome Endopeptidase Complex, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-mdm2, RNA, Messenger, Rats, Serine, Time Factors, Transfection, Tumor Suppressor Protein p53, Ubiquitination, Cell Line, Fibroblasts, Myoblasts, Cardiac, Animals, Mice, Knockout, Mice, Rats, Cardiomegaly, Disease Models, Animal, Deferoxamine, Morpholines, Chromones, Proteasome Endopeptidase Complex, Serine, RNA, Messenger, Protein Kinase Inhibitors, Transfection, Cell Size, Phosphorylation, Time Factors, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-mdm2, Hypoxia-Inducible Factor 1, alpha Subunit, Ubiquitination, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Animals, Cardiomegaly, Cell Line, Cell Size, Chromones, Deferoxamine, Disease Models, Animal, Fibroblasts, Hypoxia-Inducible Factor 1, alpha Subunit, Mice, Mice, Knockout, Morpholines, Myoblasts, Cardiac, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Phosphorylation, Proteasome Endopeptidase Complex, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-mdm2, RNA, Messenger, Rats, Serine, Time Factors, Transfection, Tumor Suppressor Protein p53, Ubiquitination, 0601 Biochemistry and Cell Biology, 1116 Medical Physiology, Biochemistry & Molecular Biology, 0601 Biochemistry and Cell Biology, 1116 Medical Physiology, Biochemistry & Molecular Biology
URI:	https://e-space.mmu.ac.uk/id/eprint/632805
DOI:	https://doi.org/10.1002/jcp.21980
ISSN	0021-9541
e-ISSN	1097-4652

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