Regulation of mammalian target of rapamycin activity in PTEN-inactive prostate cancer cells by I kappa B kinase alpha.
The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, and energy metabolism at least partly through its ability to regulate mRNA translation. mTOR is activated downstream of growth factors, insulin, and Akt-dependent signaling associated with oncoprotein expression or loss of the tumor-suppressor PTEN. In this regard, mTOR activity is associated with cancer cell growth and survival. Here, we have explored an involvement of the I kappa B kinase (IKK) pathway, associated with nuclear factor-kappaB activation, in controlling mTOR activity. The experiments show that IKK alpha controls mTOR kinase activity in Akt-active, PTEN-null prostate cancer cells, with less involvement by IKK beta. In these cells, IKK alpha associates with mTOR, as part of the TORC1 complex, in an Akt-dependent manner. Additionally, IKKalpha is required for efficient induction of mTOR activity downstream of constitutively active Akt expression. The results indicate a novel role for IKK alpha in controlling mTOR function in cancer cells with constitutive Akt activity.
Dan
Han C
HC
Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27599, USA.
Adli
Mazhar
M
Baldwin
Albert S
AS
D000818:Animals; D002460:Cell Line; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011494:Protein Kinases / Q000096:biosynthesis* / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000378:metabolism
C500984:CRTC1 protein, human; D012333:RNA, Messenger; D014157:Transcription Factors; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase; D051059:PTEN Phosphohydrolase