Convergence of p53 and Transforming Growth Factor β (TGFβ) Signaling on Activating Expression of the Tumor Suppressor Gene maspin in Mammary Epithelial Cells

Wang, Shizhen Emily; Narasanna, Archana; Whitell, Corbin W.; Wu, Frederick Y.; Friedman, David B.; Arteaga, Carlos L.

doi:10.1074/jbc.m608499200

Cited by 41TGF-β signaling in diseasesMechanisms of cancer metastasisCancer-related Molecular Pathways

Convergence of p53 and Transforming Growth Factor β (TGFβ) Signaling on Activating Expression of the Tumor Suppressor Gene maspin in Mammary Epithelial Cells

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Wang, Shizhen Emily, Narasanna, Archana, Whitell, Corbin W., Wu, Frederick Y., Friedman, David B., Arteaga, Carlos L.·2007·Journal of Biological Chemistry

DOI 10.1074/jbc.m608499200PMC PMC4015524

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Abstract

Using two-dimensional difference gel electrophoresis, we identified the tumor suppressor gene maspin as a transforming growth factor beta (TGFbeta) target gene in human mammary epithelial cells. TGFbeta up-regulatesMaspin expression both at the RNA and protein levels. This up-regulation required Smad2/3 function and intact p53-binding elements in the Maspin promoter. DNA affinity immunoblot and chromatin immunoprecipitation revealed the presence of both Smads and p53 at the Maspin promoter in TGFbeta-treated cells, suggesting that both transcription factors cooperate to induce Maspin transcription. TGFbeta did not activate Maspin-luciferase reporter in p53-mutant MDA-MB-231 breast cancer cells, which exhibit methylation of the endogenous Maspin promoter. Expression of ectopic p53, however, restored ligand-induced association of Smad2/3 with a transfected Maspin promoter. Stable transfection of Maspin inhibited basal and TGFbeta-stimulated MDA-MB-231 cell motility. Finally, knockdown of endogenous Maspin in p53 wild-type MCF10A/HER2 cells enhanced basal and TGFbeta-stimulated motility. Taken together, these data support cooperation between the p53 and TGFbeta tumor suppressor pathways in the induction of Maspin expression, thus leading to inhibition of cell migration.

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SERPINB5 is a transcriptional target of the functional convergence of p53 and TGF-h pathways.
“Interestingly, a transcriptional target of the functional convergence of these pathways is SERPINB5, the transcript most highly up-regulated in response to miR-21 knockdown (Fig. 2A; ref. 42).”
From MicroRNA-21 Targets a Network of Key Tumor-Suppressive Pathways in Glioblastoma Cells (2008) · cites this paper as [42]

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Authors: Wang, S. E., Narasanna, A., Whitell, C. W., Wu, F. Y., Friedman, D. B., & Arteaga, C. L.
Affiliations: Vanderbilt University (US)
Corresponding author: Arteaga, Carlos L.
ORCID: Wang, Shizhen Emily
Arteaga, Carlos L.
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2007-02
Volume: 282
Issue: 8
Pages: 5661-5669
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m608499200
PMC: PMC4015524
OpenAlex: W2153767510
Cited by: 41
References: 40
Citations by year: 2025: 1 · 2024: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 5 · 2013: 1 · 2012: 6
FWCI: 1.86
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 4981 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: Vanderbilt University (P30 CA68485, CA68485)
National Institutes of Health (CA68485, P50 CA98131)
Uniformed Services University of the Health Sciences
National Cancer Institute (P50 CA98131, R01 CA80195, P30 CA 68485, R01 CA-62212, R01CA080195, K99CA125892, R00CA125892, R01CA062212, P50CA098131, P30CA068485)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords: maspin, p53, TGF-beta signaling, Smad2/3, mammary epithelial cells, tumor suppressor, transcriptional regulation, promoter methylation, cell motility, breast cancer, MDA-MB-231 cells, p53 mutant cells
MeSH terms: Cell Movement, Epithelial Cells, Humans, Promoter Regions, Genetic, Signal Transduction, Transcriptional Activation, Serpins, Up-Regulation, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Mammary Glands, Human, Cell Line, Tumor, Smad2 Protein, Smad3 Protein

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Convergence of p53 and Transforming Growth Factor β (TGFβ) Signaling on Activating Expression of the Tumor Suppressor Gene maspin in Mammary Epithelial Cells

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