Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress

Kirshner, J, Jobling, MF, Pajares, MJ, Ravani, SA, Glick, AB, Lavin, MJ, Koslov, S, Shiloh, Y and Barcellos-Hoff, MH (2006) Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress. Cancer Research, 66 22: 10861-+. doi:10.1158/0008-5472.CAN-06-2565


Author Kirshner, J
Jobling, MF
Pajares, MJ
Ravani, SA
Glick, AB
Lavin, MJ
Koslov, S
Shiloh, Y
Barcellos-Hoff, MH
Title Inhibition of transforming growth factor-beta 1 signaling attenuates ataxia telanglectasia mutated activity in response to genotoxic stress
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
Publication date 2006-01-01
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-06-2565
Volume 66
Issue 22
Start page 10861
End page +
Total pages 9
Editor F. J. Rauscher III
Place of publication Philadelphia, U.S.A.
Publisher American Association for Cancer Research
Collection year 2006
Language eng
Subject C1
320305 Medical Biochemistry - Proteins and Peptides
730108 Cancer and related disorders
Abstract Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor beta (TGF beta)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGF beta inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgf beta 1 nail murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGF beta type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced gamma H2AX radiation-induced foci; and increased radiosensitivity compared with TGF beta competent cells. We determined that loss of TGF beta signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGF beta restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgf beta 1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGF beta may be used to advantage in cancer therapy.
Keyword Oncology
Growth-factor-beta
Double-strand Breaks
Cell-cycle Checkpoints
Dna-damage
Tgf-beta
Mammary-gland
Ionizing-radiation
Gene-expression
In-vitro
Atm
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2007 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 20:07:39 EST