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Transforming growth factor beta 1 suppresses genomic instability independent of a G1 arrest, p53, and Rb
A B Glick1, W C Weinberg, I H Wu
1Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, Bethesda, Maryland 20892, USA.
Abstract:
Alterations in expression of or responsiveness to transforming growth factor beta (TGF-beta) are frequently found in human and animal epithelial cancers and are though to be important for loss of growth control in the neoplastic cell. We show here that keratinocyte cell lines from mice with a targeted deletion of the TGF-beta 1 gene have significantly increased frequencies of gene amplification in response to the drug N-phosphonoacetyl-L-aspartate (PALA) compared to TGF-beta 1-expressing control keratinocyte cell lines. In contrast to the control lines, the PALA-mediated G1 arrest did not occur in the TGF-beta 1 null keratinocytes despite the presence of wild-type p53 in both genotypes. Exogenous TGF-beta 1 suppresses gene amplification in the null keratinocytes at concentrations that do not cause a G1 growth arrest and in human tumor cell lines that are insensitive to TGF-beta 1-mediated growth inhibition. The pathway of TGF-beta 1 suppression is independent of the p53 and Rb genes, but requires an intact TGF-beta type II receptor. These studies reveal a novel TGF-beta-mediated pathway regulating genomic stability and suggest that defects in TGF-beta signaling may have profound effects on tumor progression independent of cell proliferation.
Insights
Transforming growth factor beta 1 (TGF-β1) loss increases gene amplification in cancer cells. TGF-β1 signaling, independent of cell cycle arrest, maintains genomic stability.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Transforming growth factor beta (TGF-β) signaling alterations are common in epithelial cancers.
- TGF-β is implicated in the loss of growth control in neoplastic cells.
Purpose of the Study:
- To investigate the role of TGF-β1 in maintaining genomic stability.
- To explore the mechanism by which TGF-β1 suppresses gene amplification.
Main Methods:
- Utilized gene-targeted deletion of TGF-β1 in mouse keratinocytes.
- Assessed gene amplification frequencies in response to N-phosphonoacetyl-L-aspartate (PALA).
- Investigated the involvement of p53, Rb, and TGF-β type II receptor pathways.
Main Results:
- TGF-β1 null keratinocytes showed increased gene amplification frequency compared to controls.
- PALA-induced G1 arrest was absent in TGF-β1 null keratinocytes.
- Exogenous TGF-β1 suppressed gene amplification independently of G1 arrest and p53/Rb, requiring TGF-β type II receptor.
Conclusions:
- TGF-β1 plays a novel role in regulating genomic stability.
- Defects in TGF-β signaling can promote tumor progression independently of cell proliferation.