Nutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha = Nutlin3가 HIF-1a의 FIH 연관 비활성화로를 자극하여 암의 저산소 적응을 방해

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dc.contributor.authorY M Lee-
dc.contributor.authorJ H Lim-
dc.contributor.authorY S Chun-
dc.contributor.authorH E Moon-
dc.contributor.authorMyung Kyu Lee-
dc.contributor.authorL E Huang-
dc.contributor.authorJ W Park-
dc.date.accessioned2017-04-19T09:15:34Z-
dc.date.available2017-04-19T09:15:34Z-
dc.date.issued2009-
dc.identifier.issn0143-3334-
dc.identifier.uri10.1093/carcin/bgp196ko
dc.identifier.urihttps://oak.kribb.re.kr/handle/201005/9229-
dc.description.abstractThe interplay among hypoxia-inducible factor 1-alpha (HIF-1α), p53 and human orthologue of murine double minute 2 (Hdm2) has been introduced as a key event in tumor promotion and angiogenesis. Recently, nutlin-3, a small-molecule antagonist of Hdm2, was demonstrated to inhibit the HIF-1-mediated vascular endothelial growth factor production and tumor angiogenesis. Yet, the mechanism by which nutlin-3 inhibits HIF-1 is an open question. We here addressed the mode-of-action of nutlin-3 with respect to the HIF-1α-p53-Hdm2 interplay. The effect of nutlin-3 on HIF-1α function was examined by reporter analyses, immunoprecipitation and immunoblotting. Nutlin-3 downregulated HIF-1α, which occurred p53-dependently but von Hippel-Lindau-independently. On the contrary, nutlin-3 blunted the hypoxic induction of vascular endothelial growth factor by inactivating HIF-1 even in p53-null cells. The C-terminal transactivation domain (CAD) of HIF-1α was inactivated by nutlin-3, and furthermore, the factor-inhibiting hypoxia-inducible factor (FIH) hydroxylation of Asn803 was required for the nutlin-3 action. In terms of protein interactions, Hdm2 competed with FIH in CAD binding and inhibited the Asn803 hydroxylation both in vivo and in vitro, which facilitated p300 recruitment. Moreover, nutlin-3 reinforced the FIH binding and Ans803 hydroxylation by inhibiting Hdm2. In conclusion, Hdm2 functionally activates HIF-1 by inhibiting the FIH interaction with CAD, and the Hdm2 inhibition by nutlin-3 results in HIF-1 inactivation and vascular endothelial growth factor suppression. The interplays among HIF-1α, Hdm2, FIH and p300 could be potential targets for treating tumors overexpressing HIF-1α.-
dc.publisherOxford Univ Press-
dc.titleNutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha = Nutlin3가 HIF-1a의 FIH 연관 비활성화로를 자극하여 암의 저산소 적응을 방해-
dc.title.alternativeNutlin-3, an Hdm2 antagonist, inhibits tumor adaptation to hypoxia by stimulating the FIH-mediated inactivation of HIF-1alpha-
dc.typeArticle-
dc.citation.titleCarcinogenesis-
dc.citation.number10-
dc.citation.endPage1775-
dc.citation.startPage1768-
dc.citation.volume30-
dc.contributor.affiliatedAuthorMyung Kyu Lee-
dc.contributor.alternativeName이윤미-
dc.contributor.alternativeName임지홍-
dc.contributor.alternativeName전양숙-
dc.contributor.alternativeName문효은-
dc.contributor.alternativeName이명규-
dc.contributor.alternativeNameHuang-
dc.contributor.alternativeName박종완-
dc.identifier.bibliographicCitationCarcinogenesis, vol. 30, no. 10, pp. 1768-1775-
dc.identifier.doi10.1093/carcin/bgp196-
dc.description.journalClassY-
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