TRANSFORMING GROWTH-FACTOR BETA(1) SUPPRESSES GENOMIC INSTABILITY INDEPENDENT OF A G(1) ARREST, P53, AND RB

Alterations in expression of or responsiveness to transforming growth factor beta (TGF-beta) are frequently found in human and animal epithe lial cancers and are thought to be important for loss of growth contro l in the neoplastic cell, We show here that keratinocyte cell lines fr om mice with a targeted deletion of the TGF-beta 1 gene have significa ntly increased frequencies of gene amplification in response to the dr ug N-phosphonacetyl-L-aspartate (PALA) compared to TGF-beta 1-expressi ng control keratinocyte cell lines, In contrast to the control lines, the PALA-mediated G(1) arrest did not occur in the TGF-beta 1 null ker atinocytes despite the presence of wild-type p53 in both genotypes, Ex ogenous TGF-beta 1 suppresses gene amplification in the null keratinoc ytes at concentrations that do not cause a G(1) growth arrest and in h uman tumor cell lines that are insensitive to TGF-beta 1-mediated grow th inhibition, The pathway of TGF-beta 1 suppression is independent of the p53 and Rb genes, but requires an intact TGF-beta type II recepto r. These studies reveal a novel TGF-beta-mediated pathway regulating g enomic stability and suggest that defects in TGF-beta signaling may ha ve profound effects on tumor progression independent of cell prolifera tion.