A downstream kinase of the mammalian target of rapamycin, p70S6K1, regulates human double minute 2 protein phosphorylation and stability.
Human double minute 2 (HDM2) is an oncoprotein overexpressed in many human cancers. HDM2 expression is regulated at multiple levels in cells. Phosphorylation of HDM2 plays an important role in its post-translational regulation. In this study, we have shown that the phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, and the mammalian target of rapamycin (mTOR) inhibitor, rapamycin, have similar effects on the inhibition of HDM2 phosphorylation and protein turnover. Rapamycin inhibited p70S6K1, but not AKT activation, indicating that rapamycin affects HDM2 phosphorylation via an AKT-independent mechanism. Rapamycin also decreased HDM2 protein stability. Knockdown of p70S6K1 by a p70S6K1 siRNA resulted in the inhibition of HDM2 phosphorylation and a decrease in HDM2 protein turnover. Overexpression of p70S6K1 enhanced HDM2 phosphorylation and led to an increase in HDM2 protein turnover. Our results suggest that p70S6K1 regulates turnover of HDM2 protein for cancer development.
Fang
Jing
J
Department of Microbiology, Immunology and Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, West Virginia 26506-9300, USA.
Meng
Qiao
Q
Vogt
Peter K
PK
Zhang
Ruiwen
R
Jiang
Bing-Hua
BH
D002867:Chromones / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
D002867:Chromones; D009025:Morpholines; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D011494:Protein Kinases; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus