Placental transforming growth factor-beta is a downstream mediator of the growth arrest and apoptotic response of tumor cells to DNA damage and p53 overexpression

The p53 tumor suppressor gene and members of the transforming growth factor -beta (TGF-beta) superfamily play central roles in signaling cell cycle arr est and apoptosis (programmed cell death) in normal development and differe ntiation, as well as in carcinogenesis. Here we describe a distantly relate d member of the TGF-beta superfamily, designated placental TGF-beta (PTGF-b eta), that is upregulated in response to both p53-dependent and -independen t apoptotic signaling events arising from DNA damage in human breast cancer cells. PTGF-beta is normally expressed in placenta and at lower levels in kidney, lung, pancreas, and muscle but could not be detected in any tumor c ell line studied. The PTGF-beta promoter is activated by p53 and contains t wo p53 binding site motifs, Functional studies demonstrated that one of the se p53 binding sites is essential for p53-mediated PTGF-beta promoter induc tion and specifically binds recombinant p53 in gel mobility shift assays. P TGF-beta overexpression from a recombinant adenoviral vector (AdPTGF-beta) Led to an 80% reduction in MDA-MB-468 breast cancer cell viability and a 50 -60% reduction in other human breast cancer cell lines studied, including M CF-7 cells, which are resistant to growth inhibition by recombinant wild-ty pe p53. Like p53, PTGF-beta overexpression was seen to induce both G(1) cel l cycle arrest and apoptosis in breast tumor cells. These results provide t he first evidence for a direct functional link between p53 and the TGF-beta superfamily and implicate PTGF-beta as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeut ic cancer agents.