Nuclear receptor corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling

Fumihiko Furuya, Celine J. Guigon, Li Zhao, Changxue Lu, John A. Hanover, Sheue Yann Cheng

Research output: Contribution to journalArticle

Abstract

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 β receptor (TRβPV, hereafter referred to as PV) via physical interaction with p85α, thus contributing to thyroid carcinogenesis in a mouse model of follicular thyroid carcinoma (TRβPV/PV mouse). Since NCoR is known to modulate the actions of TRβ 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 p85α, the regulatory subunit of PI3K. Confocal fluorescence microscopy showed that both NCoR and p85α were localized in the nuclear as well as in the cytoplasmic compartments. Overexpression of NCoR in thyroid tumor cells of TRβPV/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 p85α 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.

Original languageEnglish (US)
Pages (from-to)6116-6126
Number of pages11
JournalMolecular and Cellular Biology
Volume27
Issue number17
DOIs
Publication statusPublished - Sep 2007
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this