• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


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


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


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