title: New tricks for an old fox: impact of TGFβ on the DNA damage response and genomic stability.
abstract: Transforming growth factor-β (TGFβ) is a well-known master regulator of cellular proliferation and is a critical factor in the maintenance of tissue homeostasis. TGFβ is classically defined as a tumor suppressor that functions in the early stages of carcinogenesis, yet paradoxically it functions as a tumor promoter in established cancers. Less well studied is its role in maintaining genomic stability through its participation in the DNA damage response (DDR). Deletion of Tgfb1 in murine epithelium increases genomic instability (GIN) as measured by gene amplification, aneuploidy, and centrosome aberrations; likewise, GIN is increased by depleting the TGFβ ligand or inhibiting TGFβ pathway signaling in human epithelial cells. Subsequent studies demonstrated that TGFβ depletion compromises cell survival in response to radiation and impairs activation of the DDR because of severely reduced activity of ataxia telangiectasia mutated (ATM), a serine/threonine protein kinase that is rapidly activated by DNA double-strand breaks. The SMAD transcription factors are intermediaries in the crosstalk between the TGFβ and ATM pathways in the DDR. Recent studies have shown that SMAD2 and SMAD7 participate in the DDR in a manner dependent on ATM or TGFβ receptor type I, respectively, in human fibroblasts and epithelial cells. Understanding the role of TGFβ in the DDR and suppressing GIN is important to understanding its seemingly paradoxical roles in tumorigenesis and thus has therapeutic implications for improving the response to DNA damage-inducing therapy.
authors.affiliation: Department of Radiation Oncology, New York University School of Medicine, 566 First Avenue, New York, NY 10016, USA. barcem01@nyumc.org francis.cucinotta@unlv.edu.
authors.forename: Mary Helen
authors.initials: MH
authors.lastname: Barcellos-Hoff
authors.affiliation: Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, 4505 Maryland Parkway, Box 453037, Las Vegas, NV 89154-3037, USA. barcem01@nyumc.org francis.cucinotta@unlv.edu.
authors.forename: Francis A
authors.initials: FA
authors.lastname: Cucinotta
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D053960:DNA Breaks; D004249:DNA Damage; D004847:Epithelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005784:Gene Amplification; D042822:Genomic Instability; D023281:Genomics; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D049490:Systems Biology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
chemical_list: C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins