1. CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence
- Author
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Cheng-Wen Wu, Kao Yr, Hsu Cf, Yi-Shing Shieh, Hsu Hs, Yu-Ting Chou, Shih Hwa Chiou, Lee Cc, Wang Yh, Pang St, Hsieh Ch, and Chung Ch
- Subjects
Cyclin-Dependent Kinase Inhibitor p21 ,Transcriptional Activation ,Cell signaling ,medicine.medical_treatment ,Transplantation, Heterologous ,Down-Regulation ,Mice, Nude ,Histone Deacetylase 1 ,Biology ,Proto-Oncogene Proteins c-myc ,Transactivation ,Mice ,Downregulation and upregulation ,Transforming Growth Factor beta ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Molecular Biology ,Cellular Senescence ,Cell Proliferation ,Original Paper ,Cell growth ,Cell Biology ,Transforming Growth Factor alpha ,HDAC1 ,E2F Transcription Factors ,ErbB Receptors ,Repressor Proteins ,Cytokine ,Cancer research ,Trans-Activators ,Signal transduction ,Transforming growth factor ,Signal Transduction - 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 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.
- Published
- 2012