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CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence.

ABSTRACT: Transforming growth factor-? (TGF-?)-induced proliferation and transforming growth factor-? (TGF-?)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYC-interacting transcriptional modulator, responds to TGF-? induction and TGF-? suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-? induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21(CIP1). CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC-HDAC1 complex formation. TGF-? stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21(CIP1) suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/p21(CIP1) signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF-? and TGF-?-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.

SUBMITTER: Chou YT 

PROVIDER: S-EPMC3504715 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence.

Chou Y-T YT   Hsieh C-H CH   Chiou S-H SH   Hsu C-F CF   Kao Y-R YR   Lee C-C CC   Chung C-H CH   Wang Y-H YH   Hsu H-S HS   Pang S-T ST   Shieh Y-S YS   Wu C-W CW  

Cell death and differentiation 20120720 12

Transforming growth factor-α (TGF-α)-induced proliferation and transforming growth factor-β (TGF-β)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYC-interacting transcriptional modulator, responds to TGF-α induction and TGF-β suppression to orchestrate cellular proliferation and qui  ...[more]

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