Journal article
TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer
The Journal of clinical investigation, Vol.120(1), pp.290-302
2010
DOI: 10.1172/JCI39194
PMCID: PMC2798681
PMID: 19955655
Abstract
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.
Details
- Title: Subtitle
- TGF-β1-induced expression of human Mdm2 correlates with late-stage metastatic breast cancer
- Creators
- Shinako ArakiXian Jin XieDavid A BoothmanJacob A EitelChristopher N BatuelloKhadijeh Bijangi-VishehsaraeiKaren E PollokLindsey D MayoDavid Danielpour
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.120(1), pp.290-302
- Publisher
- American Society for Clinical Investigation
- DOI
- 10.1172/JCI39194
- PMID
- 19955655
- PMCID
- PMC2798681
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Language
- English
- Date published
- 2010
- Academic Unit
- Preventive and Community Dentistry; Biostatistics; Dental Research
- Record Identifier
- 9983917682802771
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