title: Distinct roles of transforming growth factor-β signaling and transforming growth factor-β receptor inhibitor SB431542 in the regulation of p21 expression.
abstract: Transforming growth factor-β (TGF-β) has both tumor suppressive and oncogenic activities. Autocrine TGF-β signaling supports tumor survival and growth in certain types of cancer, and the TGF-β signaling pathway is a potential therapeutic target for these types of cancer. TGF-β induces p21 expression, and p21 is considered as an oncogene as well as a tumor suppressor, due to its anti-apoptotic activity. Thus, we hypothesized that autocrine TGF-β signaling maintains the expression of p21 at levels that can support cell growth. To verify this hypothesis, we sought to examine p21 expression and cell growth in various cancer cells following the inhibition of autocrine TGF-β signaling using siRNAs targeting TGF-β signaling components and SB431542, a TGF-β receptor inhibitor. Results from the present study show that p21 expression and cell growth were reduced by knockdown of TGF-β signaling components using siRNA in MDA-MB231 and A549 cells. Cell growth was also reduced in p21 siRNA-transfected cells. Downregulation of p21 expression induced cellular senescence in MDA-MB231 cells but did not induce apoptosis in both cells. These data suggest that autocrine TGF-β signaling is required to sustain p21 levels for positive regulation of cell cycle. On the other hand, treatment with SB431542 up-regulated p21 expression while inhibiting cell growth. The TGF-β signaling pathway was not associated with the SB431542-mediated induction of p21 expression. Specificity protein 1 (Sp1) was downregulated by treatment with SB431542, and p21 expression was increased by Sp1 knockdown. These findings suggest that downregulation of Sp1 expression is responsible for SB43154-induced p21 expression.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea. Electronic address: k4119@yonsei.ac.kr.
authors.forename: Bon-Hun
authors.initials: BH
authors.lastname: Koo
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea. Electronic address: freakangel@naver.com.
authors.forename: Yeaji
authors.initials: Y
authors.lastname: Kim
authors.affiliation: R & D Center, EyeGene Inc., Seoul 120-113, Republic of Korea. Electronic address: white@eyegene.co.kr.
authors.forename: Yang
authors.initials: Y
authors.lastname: Je Cho
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Republic of Korea. Electronic address: dskim@yonsei.ac.kr.
authors.forename: Doo-Sik
authors.initials: DS
authors.lastname: Kim
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019556:COS Cells; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D002522:Chlorocebus aethiops; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: Cycloheximide (PubChem CID: 6197); MG132 (PubChem CID: 462382); SB431542; SB431542 (PubChem CID: 4521392); SP600125 (PubChem CID: 8515); Specificity protein 1 (Sp1); TGF-β; p21