TGF-β1–induced expression of human Mdm2 correlates with late-stage metastatic breast cancer
Year: 2009
Type: article
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.
DOI: 10.1172/jci39194
Institutions: Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Indiana University Indianapolis, Indiana University Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indiana University – Purdue University Indianapolis, Case Comprehensive Cancer Center, Case Western Reserve University, Indiana University
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Awards: G1098105398, Ku70 Binding Protein-5 (KUB5), a Novel Factor in Nonhomologous End Joining, G222768804, Center for High-Throughput Minimally-Invasive Radiation Biodosimetry, G5520316217, G561675067, Regulation of Mdm2 compartmentalization, Use of Beta-lapachone for Lung Cancer Chemotherapy, UT Southwestern Medical Center Simmons Comprehensive Cancer Center
OpenAlex ID: W2124433932