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

Y. T. Chou, C. H. Hsieh, S. H. Chiou, C. F. Hsu, Y. R. Kao, C. C. Lee, C. H. Chung, Y. H. Wang, H. S. Hsu, S. T. Pang, Y. S. Shieh, C. W. Wu

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40 引文 斯高帕斯(Scopus)

摘要

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 quiescence, respectively. Upon TGF-α 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 MYCHDAC1 complex formation. TGF-β 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-α and TGF-β-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.

原文英語
頁(從 - 到)2015-2028
頁數14
期刊Cell Death and Differentiation
19
發行號12
DOIs
出版狀態已發佈 - 十二月 2012

ASJC Scopus subject areas

  • 分子生物學
  • 細胞生物學

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