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TGF-beta1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer.

The E3 ubiquitin ligase human murine double minute (HDM2) is overexpressed in 40%-80% of late-stage metastatic cancers in the absence of gene amplification. Hdm2 regulates p53 stability via ubiquitination and has also been implicated in altering the sensitivity of cells to TGF-beta1. Whether TGF-beta1 signaling induces Hdm2 expression leading to HDM2-mediated destabilization of p53 has not been investigated. In this study, we report that TGF-beta1-activated SMA- and MAD3 (Smad3/4) transcription factors specifically bound to the second promoter region of HDM2, leading to increased HDM2 protein expression and destabilization of p53 in human cancer cell lines. Additionally, TGF-beta1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithelial cells during epithelial-to-mesenchymal transition (EMT). Furthermore, histological analyses of human breast cancer samples demonstrated that approximately 65% of late-stage carcinomas were positive for activated Smad3 and HDM2, indicating a strong correlation between TGF-beta1-mediated induction of HDM2 and late-stage tumor progression. Identification of Hdm2 as a downstream target of TGF-beta1 represents a critical prosurvival mechanism in cancer progression and provides another point for therapeutic intervention in late-stage cancer.

Pubmed ID: 19955655

Authors

  • Araki S
  • Eitel JA
  • Batuello CN
  • Bijangi-Vishehsaraei K
  • Xie XJ
  • Danielpour D
  • Pollok KE
  • Boothman DA
  • Mayo LD

Journal

The Journal of clinical investigation

Publication Data

January 6, 2010

Associated Grants

  • Agency: NIAID NIH HHS, Id: 5U19AI067773-04
  • Agency: NCI NIH HHS, Id: P30CA08709
  • Agency: NCI NIH HHS, Id: P30CA142543
  • Agency: NCI NIH HHS, Id: R01 CA102792
  • Agency: NCI NIH HHS, Id: R01 CA109262
  • Agency: NCI NIH HHS, Id: R01 CA139217

Mesh Terms

  • Apoptosis
  • Breast Neoplasms
  • Female
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Imidazoles
  • Neoplasm Staging
  • Piperazines
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-mdm2
  • Smad3 Protein
  • Transforming Growth Factor beta1
  • Tumor Suppressor Protein p53