CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence.
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.
Institute of Biomedical Sciences, Academia Sinica, Taipei, ROC.
Y-T
YT
Chou
C-H
CH
Hsieh
S-H
SH
Chiou
C-F
CF
Hsu
Y-R
YR
Kao
C-C
CC
Lee
C-H
CH
Chung
Y-H
YH
Wang
H-S
HS
Hsu
S-T
ST
Pang
Y-S
YS
Shieh
C-W
CW
Wu
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015536:Down-Regulation; D050684:E2F Transcription Factors / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D056284:Histone Deacetylase 1 / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D016211:Transforming Growth Factor alpha / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014183:Transplantation, Heterologous
C486381:CITED2 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050684:E2F Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D015534:Trans-Activators; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D066246:ErbB Receptors; D056284:Histone Deacetylase 1