Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 120, Issue 1, Pages 290-302Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI39194
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Funding
- NIH [R01 CA 109262, 5U19Al067773-04]
- Department of Energy [DE-FG02-09ER64789]
- Immunohistochemistry and Biological Microscopy Cores at the Simon Cancer Center, Indiana University [NIH P30CA08709]
- Biostatistics Core, Simmons Comprehensive Cancer Center, University of Texas Southwestern [NIH P30CA142543]
- NATIONAL CANCER INSTITUTE [R01CA109262, P30CA142543, R01CA102792, R01CA139217] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U19AI067773] Funding Source: NIH RePORTER
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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-beta 1. Whether TGF-beta 1 signaling induces Hdm2 expression leading to HDM2-mediated destabilization of p53 has not been investigated. In this study, we report that TGF-beta 1-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-beta 1 expression led to Smad3 activation and murine double minute 2 (Mdm2) expression in murine mammary epithethial 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-beta 1-mediated induction of HDM2 and late-stage tumor progression. Identification of Hdm2 as a downstream target of TGF-beta 1 represents a critical prosurvival mechanism in cancer progression and provides another point for therapeutic mtervention in late-stage cancer.
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