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

Transforming growth factor-alpha (TGF-alpha)-induced proliferation and transforming growth factor-beta (TGF-beta)-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-alpha induction and TGF-beta suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-alpha 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-beta 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-alpha and TGF-beta-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome. Cell Death and Differentiation (2012) 19, 2015-2028; doi:10.1038/cdd.2012.91; published online 20 July 2012