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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Zhu, Yan Regunath, Kausik Jacq, Xavier Prives, Carol |
| Description | Country affiliation: United States Author Affiliation: Zhu Y ( Department of Biological Sciences, Columbia University, New York, New York 10027, USA.) |
| Abstract | 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 ß-activated kinase 1 (TAK1)-binding protein 1 (TAB1), an activator of TAK1 and of p38 , 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, p38 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. |
| File Format | HTM / HTML |
| ISSN | 08909369 |
| e-ISSN | 15495477 |
| DOI | 10.1101/gad.212258.112 |
| Journal | Genes & Development |
| Issue Number | 16 |
| Volume Number | 27 |
| Language | English |
| Publisher | Cold Spring Harbor Laboratory Press |
| Publisher Date | 2013-08-15 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Molecular Discipline Biology__semicolon__developmental Discipline Biology__semicolon__genetics__semicolon__cell Discipline Biology Adaptor Proteins, Signal Transducing Metabolism Antineoplastic Agents Pharmacology Cell Death Drug Effects Cisplatin Gene Expression Regulation, Neoplastic Oncogene Proteins Cell Line, Tumor Gene Knockdown Techniques Hct116 Cells Mitogen-activated Protein Kinase 14 Nuclear Proteins Genetics Phosphorylation Proteolysis Proto-oncogene Proteins Proto-oncogene Proteins C-bcl-2 Proto-oncogene Proteins C-mdm2 Signal Transduction Tumor Suppressor Protein P53 Ubiquitination Research Support, N.i.h., Extramural |
| Content Type | Text |
| Resource Type | Article |
| Subject | Genetics Developmental Biology |
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