Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell death and differentiation, 2012-12, Vol.19 (12), p.2015-2028

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 MYC-HDAC1 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.