{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:11:31Z","timestamp":1791263491765,"version":"4.1.0"},"reference-count":16,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2009,11,30]],"date-time":"2009-11-30T00:00:00Z","timestamp":1259539200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2010,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cross\u2010talk between the two transcription factors, p53 and hypoxia inducible factor 1\u03b1 (HIF1A), is important in different pathophysiological conditions (Hammond and Giaccia, 2006, Clin Cancer Res 12:5007\u20135009) 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\u2013448). In order to investigate the mechanism of p53\u2010induced HIF1A degradation, we used the established in vitro model of deferroxamine (DFX)\u2010induced HIF1A accumulation in H9c2 cardiac cells (Sano et al., 2007, Nature 446:444\u2013448). Here, we report that opposite to HIF1A accumulation following exposure to DFX, prolonged DFX\u2010induced p53 activation and HIF1A protein decrease, without any change in <jats:italic>Hif1a<\/jats:italic> mRNA. HIF1A protein decrease accompanied upregulated HIF1A ubiquitination. MDM2, an ubiquitin E3 ligase target gene of p53, was upregulated following prolonged DFX, but using <jats:italic>p53<\/jats:italic>\/<jats:italic>Mdm2<\/jats:italic> double\u2010null 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\u2010Akt<jats:sup>ser473<\/jats:sup> 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\u2010induced HIF1A degradation is not exclusively MDM2\u2010mediated, but reversible by PKB\/Akt phosphorylation. J. Cell. Physiol. 222: 635\u2013639, 2010. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.21980","type":"journal-article","created":{"date-parts":[[2009,11,30]],"date-time":"2009-11-30T14:34:26Z","timestamp":1259591666000},"page":"635-639","source":"Crossref","is-referenced-by-count":25,"title":["PKB\/Akt activation inhibits p53\u2010mediated HIF1A degradation that is independent of MDM2"],"prefix":"10.1002","volume":"222","author":[{"given":"Mun\u2010Kit","family":"Choy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mehregan","family":"Movassagh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R.","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger S.\u2010Y.","family":"Foo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,11,30]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C200694200"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2007.04.003"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(01)00507-4"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609046200"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0613"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1059796"},{"key":"e_1_2_6_8_1","first-page":"363","article-title":"Phosphatidylinositol 3\u2010kinase signaling controls levels of hypoxia\u2010inducible factor 1","volume":"12","author":"Jiang BH","year":"2001","journal-title":"Cell Growth Differ"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.01.001"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M705015200"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/20459"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/378203a0"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M609186200"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.14.1.34"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05602"},{"key":"e_1_2_6_16_1","first-page":"1541","article-title":"Modulation of hypoxia\u2010inducible factor 1alpha expression by the epidermal growth factor\/phosphatidylinositol 3\u2010kinase\/PTEN\/AKT\/FRAP pathway in human prostate cancer cells: Implications for tumor angiogenesis and therapeutics","volume":"60","author":"Zhong H","year":"2000","journal-title":"Cancer Res"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.14.4.391"}],"container-title":["Journal of Cellular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fjcp.21980","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.21980","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T03:17:01Z","timestamp":1696907821000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcp.21980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,11,30]]},"references-count":16,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2010,3]]}},"alternative-id":["10.1002\/jcp.21980"],"URL":"https:\/\/doi.org\/10.1002\/jcp.21980","archive":["Portico"],"relation":{},"ISSN":["0021-9541","1097-4652"],"issn-type":[{"value":"0021-9541","type":"print"},{"value":"1097-4652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,11,30]]}}}