Failure to prolyl hydroxylate hypoxia-inducible factor α phenocopies VHL inactivation in vivo

被引:197
作者
Kim, William Y.
Safran, Michal
Buckley, Marshall R. M.
Ebert, Benjamin L.
Glickman, Jonathan
Bosenberg, Marcus
Regan, Meredith
Kaelin, William G., Jr.
机构
[1] Harvard Univ, Sch Med, Dept Med Oncol, Dana Farber Canc Inst, Boston, MA 02215 USA
[2] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02215 USA
[3] MIT, Broad Inst, Cambridge, MA USA
[4] Harvard Univ, Sch Med, Dept Pathol, Brigham & Womens Hosp, Boston, MA 02215 USA
[5] Univ Vermont, Dept Pathol, Burlington, VT USA
[6] Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA USA
[7] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA
[8] Howard Hughes Med Inst, Chevy Chase, MD USA
关键词
hypoxia-inducible factor; prolyl hydroxylase; von Hippel-Lindau;
D O I
10.1038/sj.emboj.7601300
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Many functions have been assigned to the von Hippel-Lindau tumor suppressor gene product (pVHL), including targeting the alpha subunits of the heterodimeric transcription factor HIF (hypoxia-inducible factor) for destruction. The binding of pVHL to HIF alpha requires that HIFa be hydroxylated on one of two prolyl residues. We introduced HIF1 alpha and HIF2 alpha variants that cannot be hydroxylated on these sites into the ubiquitously expressed ROSA26 locus along with a Lox-stop-Lox cassette that renders their expression Cre-dependent. Expression of the HIF2a variant in the skin and liver induced changes that were highly similar to those seen when pVHL is lost in these organs. Dual expression of the HIF1a and HIF2a variants in liver, however, more closely phenocopied the changes seen after pVHL inactivation than did the HIF2a variant alone. Moreover, gene expression profiling confirmed that the genes regulated by HIF1a and HIF2a in the liver are overlapping but non- identical. Therefore, the pathological changes caused by pVHL inactivation in skin and liver are due largely to dysregulation of HIF target genes.
引用
收藏
页码:4650 / 4662
页数:13
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