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
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 me...
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Published in | The Journal of biological chemistry Vol. 275; no. 26; p. 20127 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Society for Biochemistry and Molecular Biology
30.06.2000
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Online Access | Get full text |
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Abstract | 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 50â60% 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. |
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AbstractList | 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 50â60% 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. |
Author | Ayeda Ayed Pei-Xiang Li Cheryl Arrowsmith Henry J. Klamut Richard C. Austin Duc Ngo Jeffrey Wong Anthony M. Brade |
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Title | 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 |
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