Convergence of p53 and transforming growth factor β (TGFβ) signaling on activating expression of the tumor suppressor gene maspin in mammary epithelial cells

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

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Using two-dimensional difference gel electrophoresis, we identified the tumor suppressor gene maspin as a transforming growth factor β (TGFβ) target gene in human mammary epithelial cells. TGFβ 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. DNAaffinity immunoblot and chromatin immunoprecipitation revealed the presence of both Smads and p53 at the Maspin promoter in TGFβ-treated cells, suggesting that both transcription factors cooperate to induce Maspin transcription. TGFβ 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 TGFβ-stimulated MDA-MB-231 cell motility. Finally, knockdown of endogenous Maspin in p53 wild-type MCF10A/HER2 cells enhanced basal and TGFβ-stimulated motility. Taken together, these data support cooperation between the p53 and TGFβ tumor suppressor pathways in the induction of Maspin expression, thus leading to inhibition of cell migration.

Original languageEnglish (US)
Pages (from-to)5661-5669
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number8
DOIs
StatePublished - Feb 23 2007

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Transforming Growth Factors
Tumor Suppressor Genes
Tumors
Breast
Genes
Epithelial Cells
Cells
Two-Dimensional Difference Gel Electrophoresis
SERPIN-B5
Cell Migration Inhibition
Methylation
Chromatin Immunoprecipitation
Transcription
Electrophoresis
Luciferases
Chromatin
Cell Movement
Transfection
Transcription Factors
Up-Regulation

ASJC Scopus subject areas

  • Biochemistry

Cite this

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.

In: Journal of Biological Chemistry, Vol. 282, No. 8, 23.02.2007, p. 5661-5669.

Research output: Contribution to journalArticle

Wang, Shizhen Emily ; Narasanna, Archana ; Whitell, Corbin W. ; Wu, Frederick Y. ; Friedman, David B. ; Arteaga, Carlos L. / Convergence of p53 and transforming growth factor β (TGFβ) signaling on activating expression of the tumor suppressor gene maspin in mammary epithelial cells. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 8. pp. 5661-5669.
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abstract = "Using two-dimensional difference gel electrophoresis, we identified the tumor suppressor gene maspin as a transforming growth factor β (TGFβ) target gene in human mammary epithelial cells. TGFβ 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. DNAaffinity immunoblot and chromatin immunoprecipitation revealed the presence of both Smads and p53 at the Maspin promoter in TGFβ-treated cells, suggesting that both transcription factors cooperate to induce Maspin transcription. TGFβ 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 TGFβ-stimulated MDA-MB-231 cell motility. Finally, knockdown of endogenous Maspin in p53 wild-type MCF10A/HER2 cells enhanced basal and TGFβ-stimulated motility. Taken together, these data support cooperation between the p53 and TGFβ tumor suppressor pathways in the induction of Maspin expression, thus leading to inhibition of cell migration.",
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