This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Furuya, F.
Right arrow Articles by Cheng, S.-y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Furuya, F.
Right arrow Articles by Cheng, S.-y.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, September 2007, p. 6116-6126, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00900-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Nuclear Receptor Corepressor Is a Novel Regulator of Phosphatidylinositol 3-Kinase Signaling{triangledown}

Fumihiko Furuya,1 Celine J. Guigon,1 Li Zhao,1 Changxue Lu,1 John A. Hanover,2 and Sheue-yann Cheng1*

Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute,1 Laboratory of Cellular Biochemistry and Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 208922

Received 21 May 2007/ Returned for modification 16 June 2007/ Accepted 23 June 2007

The nuclear receptor corepressor (NCoR) regulates the activities of DNA-binding transcription factors. Recent observations of its distribution in the extranuclear compartment raised the possibility that it could have other cellular functions in addition to transcription repression. We previously showed that phosphatidylinositol 3-kinase (PI3K) signaling is aberrantly activated by a mutant thyroid hormone ß receptor (TRßPV, hereafter referred to as PV) via physical interaction with p85{alpha}, thus contributing to thyroid carcinogenesis in a mouse model of follicular thyroid carcinoma (TRßPV/PV mouse). Since NCoR is known to modulate the actions of TRß mutants in vivo and in vitro, we asked whether NCoR regulates PV-activated PI3K signaling. Remarkably, we found that NCoR physically interacted with and competed with PV for binding to the C-terminal SH2 (Src homology 2) domain of p85{alpha}, the regulatory subunit of PI3K. Confocal fluorescence microscopy showed that both NCoR and p85{alpha} were localized in the nuclear as well as in the cytoplasmic compartments. Overexpression of NCoR in thyroid tumor cells of TRßPV/PV mouse reduced PI3K signaling, as indicated by the decrease in the phosphorylation of its immediate downstream effector, p-AKT. Conversely, lowering cellular NCoR by siRNA knockdown in tumor cells led to overactivated p-AKT and increased cell proliferation and motility. Furthermore, NCoR protein levels were significantly lower in thyroid tumor cells than in wild-type thyrocytes, allowing more effective binding of PV to p85{alpha} to activate PI3K signaling and thus contributing to tumor progression. Taken together, these results indicate that NCoR, via protein-protein interaction, is a novel regulator of PI3K signaling and could serve to modulate thyroid tumor progression.

* Corresponding author. Mailing address: Laboratory of Molecular Biology, National Cancer Institute, 37 Convent Dr., Room 5128, Bethesda, MD 20892-4264. Phone: (301) 496-4280. Fax: (301) 402-1344. E-mail: chengs{at}mail.nih.gov

{triangledown} Published ahead of print on 2 July 2007.

Molecular and Cellular Biology, September 2007, p. 6116-6126, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.00900-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»