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J. Biol. Chem., Vol. 275, Issue 26, 20127-20135, June 30, 2000
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From the Divisions of The p53 tumor suppressor gene and members of the
transforming growth factor-
Placental Transforming Growth Factor-
Is a Downstream
Mediator of the Growth Arrest and Apoptotic Response of Tumor Cells
to DNA Damage and p53 Overexpression*
§,§,§,§
,§
Experimental Therapeutics and
¶ Molecular and Structural Biology, Ontario Cancer Institute,
Princess Margaret Hospital, University Health Network, and the
Departments of § Medical Biophysics and Radiation
Oncology, University of Toronto, Toronto, Ontario M5G 2M9 and
** Hamilton Civic Hospitals Research Centre and McMaster University,
Hamilton, Ontario L8V 1C3, Canada
(TGF-) 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- superfamily, designated placental TGF- (PTGF-), 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- 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- 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- promoter induction and specifically binds recombinant p53 in
gel mobility shift assays. PTGF- overexpression from a recombinant adenoviral vector (AdPTGF-) 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- overexpression was seen to induce both G1
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- superfamily and implicate PTGF- as an important intercellular mediator of p53 function and the cytostatic effects of
radiation and chemotherapeutic cancer agents.
*
This work was supported in part by grants from the
Foundation for Gene and Cell Therapy, the Canadian Breast Cancer
Foundation, and the Medical Research Council of Canada as well as a
Jessie Davidson Medical Research Council Fellowship (to A. M. B.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Medical
Biophysics, University of Toronto, Ontario Cancer Institute, Princess
Margaret Hospital, 610 University Ave., Rm. 10-721, Toronto, Ontario
M5G 2M9, Canada. Tel.: 416-946-2981; Fax: 416-946-2984; E-mail:
hklamut@oci.utoronto.ca.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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