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

被引：71

作者：

Chou, Y-T ^{[2
]}

Hsieh, C-H ^{[1
]}

Chiou, S-H ^{[3
,4
]}

Hsu, C-F ^{[2
]}

Kao, Y-R ^{[2
]}

Lee, C-C ^{[2
]}

Chung, C-H ^{[2
]}

Wang, Y-H ^{[5
]}

Hsu, H-S ^{[4
,7
]}

Pang, S-T ^{[6
]}

Shieh, Y-S ^{[8
]}

Wu, C-W ^{[1
,2
,4
,9
]}

机构：

[1] Natl Yang Ming Univ, Inst Microbiol & Immunol, Taipei 112, Taiwan

[2] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan

[3] Natl Yang Ming Univ, Inst Pharmacol, Taipei 112, Taiwan

[4] Natl Yang Ming Univ, Inst Clin Med, Taipei 112, Taiwan

[5] Shung Ho Hosp, Dept Urol, Div Gen Surg, Taipei, Taiwan

[6] Chang Gung Mem Hosp & Univ, Coll Med, Dept Surg, Div Urol, Tao Yuan, Taiwan

[7] Taipei Vet Gen Hosp, Dept Surg, Taipei, Taiwan

[8] Triserv Gen Hosp, Dept Oral Diag & Pathol, Taipei, Taiwan

[9] Natl Yang Ming Univ, Inst Biochem & Mol Biol, Taipei 112, Taiwan

来源：

CELL DEATH AND DIFFERENTIATION | 2012年 / 19卷 / 12期

关键词：

CITED2; MYC; cytokine; transcriptional modulator; lung cancer; GROWTH-FACTOR-BETA; NONSMALL CELL LUNG; C-MYC; TRANSCRIPTION FACTORS; BINDING-PROTEIN; GENE-EXPRESSION; FACTOR RECEPTOR; CANCER CELLS; P21; PROMOTER;

D O I：

10.1038/cdd.2012.91

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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

引用

页码：2015 / 2028

页数：14

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