Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitry.
The interdependence of p53 and MDM2 is critical for proper cell survival and cell death and, when altered, can lead to tumorigenesis. Mitogen-activated protein kinase (MAPK) signaling pathways function in a wide variety of cellular processes, including cell growth, migration, differentiation, and death. Here we discovered that transforming growth factor ... β-activated kinase 1 (TAK1)-binding protein 1 (TAB1), an activator of TAK1 and of p38α, associates with and inhibits the E3 ligase activity of MDM2 toward p53 and its homolog, MDMX. Depletion of TAB1 inhibits MDM2 siRNA-mediated p53 accumulation and p21 induction, partially rescuing cell cycle arrest induced by MDM2 ablation. Interestingly, of several agents commonly used as DNA-damaging therapeutics, only cell death caused by cisplatin is mitigated by knockdown of TAB1. Two mechanisms are required for TAB1 to regulate apoptosis in cisplatin-treated cells. First, p38α is activated by TAB1 to phosphorylate p53 N-terminal sites, leading to selective induction of p53 targets such as NOXA. Second, MDMX is stabilized in a TAB1-dependent manner and is required for cell death after cisplatin treatment. Interestingly TAB1 levels are relatively low in cisplatin-resistant clones of ovarian cells and in ovarian patient's tumors compared with normal ovarian tissue. Together, our results indicate that TAB1 is a potential tumor suppressor that serves as a functional link between p53-MDM2 circuitry and a key MAPK signaling pathway.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Antineoplastic Agents, Cell Death, Cell Line, Tumor, Cisplatin, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, HCT116 Cells, Humans, Mitogen-Activated Protein Kinase 14, Nuclear Proteins, Oncogene Proteins, Phosphorylation, Proteolysis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Tumor Suppressor Protein p53, Ubiquitination
Adaptor Proteins, Signal Transducing, Antineoplastic Agents, Cell Death, Cell Line, Tumor, Cisplatin, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, HCT116 Cells, Humans, Mitogen-Activated Protein Kinase 14, Nuclear Proteins, Oncogene Proteins, Phosphorylation, Proteolysis, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-mdm2, Signal Transduction, Tumor Suppressor Protein p53, Ubiquitination
Genes Dev.
Date: Aug. 15, 2013
PubMed ID: 23934659
View in: Pubmed Google Scholar
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