TGF-beta-induced cell-cycle arrest through the p21(WAF1/CIP1)-G1 cyclin/Cdks-p130 pathway in gastric-carcinoma cells.
Transforming growth factor-beta1 (TGF-beta) inhibits cell-cycle progression of many types of cells by arresting them in G(1)/S phase through inhibition of the active cyclin-Cdk complexes that lead to inhibition of Rb phosphorylation. In gastric-cancer cells, SNU16, TGF-beta treatment induced enhanced expression of p21(WAF1/CIP1) (p21), which inhibited the kinase activity of cyclin-D- and cyclin-E-associated Cdks and blocked p130 phosphorylation. TGF-beta also enhanced the stability of p130, suggesting that hypophosphorylation of p130 and increased stability of p130 contribute to p130-mediated G(1) arrest in gastric-cancer cells. Our results demonstrate that p21 and p130 are major downstream targets of TGF-beta in gastric-cancer cells and that a p21-G(1) cyclin/Cdks-p130/E2F pathway mediates growth inhibition by TGF-beta in these cells.
Yoo
Y D
YD
Laboratory of Experimental Therapeutics and Korea Cancer Center Hospital, Seoul, Republic of Korea. ydy@kcchsun.kcch.re.kr
Choi
J Y
JY
Lee
S J
SJ
Kim
J S
JS
Min
B R
BR
Lee
Y I
YI
Kang
Y K
YK
D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000187:drug effects
C534702:CCNG1 protein, human; C493956:CDKN1A protein, human; D056746:Cyclin G; D056766:Cyclin G1; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D010750:Phosphoproteins; D011506:Proteins; C493837:RBL2 protein, human; D016160:Retinoblastoma Protein; D050717:Retinoblastoma-Like Protein p130; D016212:Transforming Growth Factor beta; D018844:Cyclin-Dependent Kinases