Placental Transforming Growth Factor-β Is a Downstream Mediator of the Growth Arrest and Apoptotic Response of Tumor Cells to DNA Damage and p53 Overexpression

• Published in: The Journal of biological chemistry Vol. 275; no. 26; p. 20127
• Main Authors: Pei-Xiang Li, Jeffrey Wong, Ayeda Ayed, Duc Ngo, Anthony M. Brade, Cheryl Arrowsmith, Richard C. Austin, Henry J. Klamut
• Format: Journal Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology 30.06.2000
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M909580199

The p53 tumor suppressor gene and members of the transforming growth factor-β (TGF-β) superfamily play central roles in signaling cell cycle arrest and apoptosis (programmed cell death) in normal development and differentiation, as well as in carcinogenesis. Here we describe a distantly related member of the TGF-β superfamily, designated placental TGF-β (PTGF-β), that is up-regulated in response to both p53-dependent and -independent apoptotic signaling events arising from DNA damage in human breast cancer cells. PTGF-β is normally expressed in placenta and at lower levels in kidney, lung, pancreas, and muscle but could not be detected in any tumor cell line studied. The PTGF-β promoter is activated by p53 and contains two p53 binding site motifs. Functional studies demonstrated that one of these p53 binding sites is essential for p53-mediated PTGF-β promoter induction and specifically binds recombinant p53 in gel mobility shift assays. PTGF-β overexpression from a recombinant adenoviral vector (AdPTGF-β) 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 MCF-7 cells, which are resistant to growth inhibition by recombinant wild-type p53. Like p53, PTGF-β overexpression was seen to induce both G 1 cell cycle arrest and apoptosis in breast tumor cells. These results provide the first evidence for a direct functional link between p53 and the TGF-β superfamily and implicate PTGF-β as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeutic cancer agents.