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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
Open accessAbstract
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.
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“Physiological levels of circulating GDF15 are low in healthy humans but increase in disease states and during pregnancy [203] (Table 1).”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [203]
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Metadata
- Authors
- Li, P.-X., Wong, J., Ayed, A., Ngo, D., Brade, A. M., Arrowsmith, C., Austin, R. C., & Klamut, H. J.
- Affiliations
- University Health Network (CA)
- McMaster University (CA)
- Corresponding author
- Klamut, Henry J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-06
- Volume
- 275
- Issue
- 26
- Pages
- 20127-20135
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2126527070
- Cited by
- 254
- References
- 88
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2022: 3 · 2021: 8 · 2020: 13 · 2019: 10 · 2018: 10 · 2017: 9 · 2016: 6 · 2015: 11 · 2014: 9 · 2013: 10 · 2012: 12
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Medical Research Council Canada
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- TGF-beta superfamily, p53, DNA damage, apoptosis, G1 cell cycle arrest, breast cancer, p53 binding sites, promoter induction, adenoviral overexpression, radiation-induced cell death, chemotherapeutic drug resistance
- MeSH terms
- Adenoviridae, Breast Neoplasms, Cell Cycle, Cell Division, Cell Survival, DNA Damage, Genetic Vectors, Growth Substances, Humans, Pregnancy Proteins, RNA, Messenger, Time Factors, Tissue Distribution, Tumor Cells, Cultured, Blotting, Northern, Transcriptional Activation, Up-Regulation, Genes, p53, Tumor Suppressor Protein p53, Apoptosis, Sequence Analysis, DNA, DNA, Complementary
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