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
| Autor: | Richard C. Austin, Jeffrey V. Wong, Anthony Brade, Henry J. Klamut, Cheryl H. Arrowsmith, Pei-Xiang Li, Ayeda Ayed, Duc Ngo |
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| Rok vydání: | 2000 |
| Předmět: |
Transcriptional Activation
Programmed cell death DNA Complementary Time Factors Cell Survival Genetic Vectors Apoptosis Breast Neoplasms Pregnancy Proteins Biology medicine.disease_cause Biochemistry Adenoviridae Tumor Cells Cultured medicine Humans Tissue Distribution RNA Messenger Growth Substances Molecular Biology Cell Cycle Cancer Sequence Analysis DNA Cell Biology Blotting Northern Genes p53 medicine.disease Up-Regulation Transforming growth factor beta 3 Cancer cell Cancer research GDF15 Tumor Suppressor Protein p53 Carcinogenesis Cell Division DNA Damage Transforming growth factor |
| Zdroj: | Journal of Biological Chemistry. 275:20127-20135 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m909580199 |
| Popis: | The p53 tumor suppressor gene and members of the transforming growth factor-beta (TGF-beta) 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-beta superfamily, designated placental TGF-beta (PTGF-beta), 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-beta 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-beta 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-beta promoter induction and specifically binds recombinant p53 in gel mobility shift assays. PTGF-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 MCF-7 cells, which are resistant to growth inhibition by recombinant wild-type p53. Like p53, PTGF-beta 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-beta superfamily and implicate PTGF-beta as an important intercellular mediator of p53 function and the cytostatic effects of radiation and chemotherapeutic cancer agents. |
| Databáze: | OpenAIRE |
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