BRCA1 interacts with and is required for paclitaxel-induced activation of mitogen-activated protein kinase kinase kinase 3
| Autor: | Paul B. Mullan, Jennifer E. Quinn, Nuala McCabe, Richard D. Kennedy, Stewart McWilliams, Michael Carty, W. Paul Duprex, Edison T. Liu, Julia J. Gorski, D. Paul Harkin, Patrick G. Johnston, Heather N. Andrews, Paula M. Gilmore |
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| Rok vydání: | 2004 |
| Předmět: |
Cancer Research
endocrine system diseases Paclitaxel Breast Neoplasms MAP Kinase Kinase Kinase 3 Biology Mitogen-activated protein kinase kinase MAP2K7 Cell Line Tumor Humans ASK1 skin and connective tissue diseases Mitogen-Activated Protein Kinase Kinase Kinase 3 Binding Sites MAP kinase kinase kinase Cyclin-dependent kinase 4 BRCA1 Protein Cyclin-dependent kinase 2 MAP Kinase Kinase Kinases Molecular biology Antineoplastic Agents Phytogenic Protein Structure Tertiary Enzyme Activation Oncology biology.protein Cyclin-dependent kinase 9 Plasmids |
| Zdroj: | Cancer research. 64(12) |
| ISSN: | 0008-5472 |
| Popis: | BRCA1 has been implicated in a number of cellular processes, including transcriptional regulation, DNA damage repair, cell cycle arrest, and apoptosis. We identified mitogen-activated protein kinase (MAPK) kinase kinase 3 (MEKK3), an upstream regulator of the c-Jun NH2-terminal kinase/stress-activated protein kinase and p38/MAPK pathways, as a novel BRCA1-interacting protein in a yeast two-hybrid screen and confirmed the interaction by coimmunoprecipitation in mammalian cells. Deletion mapping demonstrated that amino acids 1611–1863 are required to mediate the interaction with MEKK3 in yeast. BRCA1 disease-associated mutations abrogated the interaction in yeast, and BRCA1 failed to interact with MEKK3 in BRCA1 mutant HCC1937 breast cancer cells. We demonstrate that small interfering RNA-based inhibition of endogenous BRCA1 reduces MEKK3 kinase activity and conversely that inducible expression of BRCA1 activates MEKK3 and p38/MAPK. Finally, we demonstrate using complementary approaches that BRCA1 is required for paclitaxel-induced activation of MEKK3. These data indicate that BRCA1 is a key regulator of the paclitaxel-induced stress response pathway and suggest that the ability of BRCA1 to associate with, and mediate the activation of, MEKK3 represents a potential mechanism through which this pathway is regulated. |
| Databáze: | OpenAIRE |
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