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, Cheng-Wen Wu Lee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)2015-2028
Number of pages14
JournalCell Death and Differentiation
Volume19
Issue number12
DOIs
StatePublished - 1 Dec 2012

Keywords

  • CITED2
  • MYC
  • cytokine
  • lung cancer
  • transcriptional modulator

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