TGF-β. transforming. growth factor. growth factor-β TGF-β. Transforming growth factor-β TGF-β. Smad. DNA Smad Smad cofactor. transcription factor Smad

Size: px

Start display at page:

Download "TGF-β. transforming. growth factor. growth factor-β TGF-β. Transforming growth factor-β TGF-β. Smad. DNA Smad Smad cofactor. transcription factor Smad"

Mitchell Phillips
5 years ago
Views:

1 TGF-β Smad cofactors 2 Transforming growth factor-β TGF-β TGF-β Smad Smad DNA Smad Smad cofactor TGF-β Maid Maid Smad cofactor Smad cofactor TGF-β -β signal transduction transcription factor Smad 1980 transforming growth factor-β TGF-β TGF-β transforming growth factor TGF-β 1984 TGF-β 1990 TGF-β Smad TGF-β

2 TGF-β epithelial-mesenchymal transition, EMT TGF-β TGF-β Harold Moses 2006 molecular Jekyll and Hyde of cancer 3 TGF-β TGF-β apc min adenoma adenocarcinoma progression xenograft model 4 TGF-β 1 TGF-β tumor initiating cells tumor initiating cells tumorigenicity TGF-β 5 tumor initiating cells β TGF-β Smad 9 TGF-β TGF-β 1 TGF-β tumor initiating cells TGF-β

3 TGF-β Smad cofactors 67 2 I II TGF-β II I 2 4 II I I Smad2 Smad3 C- 2 Smad2/3 1 Smad4 3 Smad / 1 Smad DNA Smad binding element, SBE AGAC 10 Smad DNA SBE DNA Smad DNA Smad Smad cofactor Smad-Smad cofactor synexpression group Smad Smad cofactor 1 TGF-β TGF-β II I 2 4 II I I Smad2 Smad3 2 Smad2/3 1 Smad4 3 Smad /

4 68 Smad cofactor Smad Smad cofactor 2 TGF-β TGF-β Smad cofactor Smad cofactor synexpression group TGF-β TGF-β Maternal Id-like molecule Maid mrna 11,12 HHM human homologue of Maid Maid 360 helix-loop-helix HLH basic HLH DNA Id-like molecule Id HLH Smad bait yeast two hybrid Maid TGF-β TGF-β Maid 13 TGF-β 2 Smad cofactors Smad A E Smad cofactor D 1 4 Smad cofactor Smad-Smad cofactor synexpression group

TGF-β Smad cofactors 69 Maid TGF-β EMT Maid Maid TGF-β Maid TGF-β TGF-β p21 WAF c-myc Maid TGF-β EMT Snail Snail Maid Maid DNA Maid TGF-β 15 Maid synexpression group Maid Smad cofactor Olig1 Smad

5 TGF-β Smad cofactors 69 Maid TGF-β EMT Maid Maid TGF-β Maid TGF-β TGF-β p21 WAF c-myc Maid TGF-β EMT Snail Snail Maid Maid DNA Maid TGF-β 15 Maid synexpression group Maid Smad cofactor Olig1 Smad Smad cofactor Smad- Smad cofactor 3 TGF-β YY-1 14 Maid Smad cofactor Smad cofactor 3 Maid Smad cofactor A Maid synespression group B Maid Smad cofactor B Olig1 Smad Smad cofactor Smad Smad cofactor

6 Smad Smad 15 Smad cofactor 2 3 Smad Hill Forkhead Mix Smad2 Smad2 16 TGF-β p21 WAF p21 WAF Smad cofactor controversial Piccolo p53 Smad HepG2 p21 WAF p53 p53 TGF-β 17 Massague HaCaT FoxO C/EBP Smad synexpression groups 18 FoxO p21 WAF Smad ChIP-Chip HaCaT 19 p21 WAF Smad Smad cofactor Ets1 Ets1 TGF-β p21 WAF Smad cofactor Smad cofactor synexpression group bhlh Olig1 Maid Smad cofactor 13 Olig1 ubiquitous Olig1 mrna DNA Olig1 TGF-β 10 Olig1 TGF-β Smad Smad-Olig1 synexpression group plasminogen activator inhibitor-1 (PAI-1), plateletderived growth factor-b (PDGF B), connective tissue growth factor (CTGF), procollagen 1 CTGF DEC1 IL-11 Olig1 TGF-β ChIP-Chip Smad2/3 Ets1 AP-2 Sp1 p53 E2F thyroid transcription factor-1 vitamin D receptor VDR Myc 19 Smad cofactor Smad cofactor Maid

7 TGF-β Smad cofactors 71 TGF-β TGF-β in vivo TGF-β tgfb1 -/- TGF-β tgfb1 +/- 20 tgfb1 +/- TGF-β 30 TGF-β TGF-β haploinsufficiency tumor suppressor TGF-β TGF-β TGF-β Smad Smad cofactor 4A TGF-β synexpression group Smad cofactor Smad Maid Smad cofactor cofactor 4B Maid Smad cofactor utilization TGF-β in vivo Smad cofactor Sp1 Olig1 ubiquitous Smad cofactor tissue- 4 Smad cofactor A Smad Smad cofactor TGF-β A Smad cofactor B C D Smad cofactor Smad cofactor A B C D TGF-β Smad cofactor B Maid Smad cofactor 3 Smad cofactor B Smad cofactor Maid C Smad cofactor TGF-β

8 72 specific Smad cofactor VDR p53 Smad cofactor / conditional Smad cofactor VDR Smad 19 Smad VDR TGF-β D 21 Smad cofactor preference Smad cofactor TGF-β cellular context Smad cofactor Maid Smad-Smad cofactor Maid Smad-Smad cofactor Smad comprehensive TGF-β Moses HL, Roberts AB: The discovery of TGF-β: A historical perspective. In: Derynck R, Miyazono K, eds. The TGF-β family. Cold Spring Harbor Laboratory Press, New York; 1 28, Siegel PM, Shu W, Cardiff RD, Muller WJ, Massague J: Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Pro Natl Acad Sci USA, 100: , Bierie B, Moses HL: TGFβ: the molecular Jekyll and Hyde of cancer. Nat Rev Cancer, 6: , Arteaga CL, McPherson JM: Development of TGF-β-based therapeutic agents: Capitalizing on TGF-β s mechanism of action and signal transduction pathways. In: Derynck R, Miyazono K, eds. The TGF-β family. Cold Spring Harbor Laboratory Press, New York; , Penuelas S, Anido J, Prieto-Sanchez RM, Folch G, Barba I, et al.: TGF-β increases glioma-initiating cell self renewal through the induction of LIF in human glioblastoma. Cancer Cell, 15: , Tang B, Yoo N, Vu M, Mamura M, Nam J-S, et al.: Transforming growth factor-β can suppress tumorigenesis through effects on the putative cancer stem or early progenitor cell and committed progeny in a breast cancer xenograft model. Cancer Res, 67: , Ohgushi M, Kuroki S, Fukamachi H, O Reilly LA, Kuida K, et al. Transforming growth factor β- dependent sequential activation of Smad, Bim, and caspase-9 mediates physiological apoptosis in gastric epithelial cells. Mol Cell Biol, 25: , Ehata S, Hanyu A, Hayashi M, Aburatani H, Kato Y, et al. Transforming growth factor-β promotes survival of mammary carcinoma cells through induction of antiapoptotic transcription factor DEC1. Cancer Res, 67: , Shi Y, Massagué J: Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell, 113: , Dennler S, Itoh S, Vivien D, ten Dijke P, Huet S, et al.: Direct binding of Smad3 and Smad4 to critical TGFβ-inducible elements in the promoter of human plasminogen activator inhibitortype 1 gene. EMBO J, 17: , Hwang SY, Oh B, Fuchtbauer A, Fuchtbauer EM, Johnson KR, et al.: maid: a maternally transcribed novel gene encoding a potential negative regulator of bhlh proteins in the mouse egg

9 TGF-β Smad cofactors 73 and zygote. Dev Dyn, 209: , Terai S, Aoki H, Thorgeirsson S: Human homologue of Maid: a dominant inhibitory helix-loophelix protein associated with liver-specific gene expression.hepatology, 32: , Ikushima H, Komuro A, Isogaya K, Shinozaki M, Hellman U, et al.: An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGFβ signalling. EMBO J, 27: , Miyazawa K, Shinozaki M, Hara T, Furuya T, Miyazono K: Two major Smad pathways in TGF-β superfamily signalling. Genes Cells, 7: , Germain S, Howell M, Esslemont GM, Hill CS:Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif. Genes Dev, 14: , Cordenonsi M, Dupont S, Maretto S, Insinga A, Imbriano C, et al.: Links between tumor supressors: p53 is required for TGF-β gene responses by cooperating with Smads. Cell, 113: , Gomis R, Alarcon C, He W, Wang Q, Seoane J, et al.: A FoxO-Smad synexpression group in human keratinocytes. Pro Natl Acad Sci USA, 103: , Koinuma D, Tsutsumi S, Kamimura N, Taniguchi H, Miyazawa K, et al: Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factor β signaling. Mol Cell Biol, 29: , Kurisaki K, Kurisaki A, Valcourt U, Terentiev AA, Pardali K, et al.: Nuclear factor YY1 inhibits transforming growth factor β- and bone morphogenetic protein-induced cell differentiation. Mol Cell Biol, 23: , Tang B, Böttinger EP, Jakowlew SB, Bagnall K, Mariano J, et al.: Transforming growth factor-β1 is a new form of tumor suppressor with true haploid insufficiency. Nat Genet, 4: , Yanagisawa J, Yanagi Y, Masuhiro Y, Suzawa M, Watanabe M, et al.: Convergence of transforming growth factor-β and vitamin D signaling pathways on SMAD transcriptional coactivators. Science, 283: , 1999.

Control of Cell Proliferation by Peptide Growth Factors. Autocrine Growth Factor Production Causes Malignant Transformation?

Control of Cell Proliferation by Peptide Growth Factors Autocrine Growth Factor Production Causes Malignant Transformation? Transforming Activities From Condition Media from a Tumor Cell Line Condition