A Cytosolic ATM/NEMO/RIP1 Complex Recruits TAK1 To Mediate the NF-κB and p38 Mitogen-Activated Protein Kinase (MAPK)/MAPK-Activated Protein 2 Responses to DNA Damage
| Autor: | Pallavi Gandhi, Sarah Morrissey, Mary Munson, Fang Xia, Sara J.S. Simonson, Angela M. Mabb, Yibin Yang, Michelle A. Kelliher, Shigeki Miyamoto, Nicole Hermance |
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| Rok vydání: | 2011 |
| Předmět: |
MAPK/ERK pathway
DNA damage SUMO-1 Protein Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins IκB kinase Protein Serine-Threonine Kinases Biology p38 Mitogen-Activated Protein Kinases Mice Animals Humans Gene Silencing RNA Small Interfering CHUK Protein kinase A Molecular Biology Cells Cultured Etoposide Mice Knockout Mitogen-Activated Protein Kinase 1 Antibiotics Antineoplastic MAP kinase kinase kinase Ubiquitin Kinase Tumor Suppressor Proteins GTPase-Activating Proteins Intracellular Signaling Peptides and Proteins NF-kappa B I-Kappa-B Kinase Articles Cell Biology MAP Kinase Kinase Kinases Antineoplastic Agents Phytogenic I-kappa B Kinase Cell biology DNA-Binding Proteins Doxorubicin Multiprotein Complexes Cancer research Tumor Suppressor Protein p53 DNA Damage |
| Zdroj: | Molecular and Cellular Biology. 31:2774-2786 |
| ISSN: | 1098-5549 |
| Popis: | In multiple tumor types, activation of the transcription factor NF-κB increases the resistance of tumor cells to anticancer therapies and contributes to tumor progression. Genotoxic stress induced by chemotherapy or radiation therapy triggers the ATM-dependent translocation of NF-κB essential modifier (NEMO), also designated IκB kinase γ (IKKγ), from the nucleus to the cytosol, resulting in IκB kinase activation by mechanisms not yet fully understood. RIP1 has been implicated in this response and found to be modified in cells with damaged DNA; however, the nature of the RIP1 modification and its precise role in the pathway remain unclear. Here, we show that DNA damage stimulates the formation of a cytosolic complex containing ATM, NEMO (IKKγ), RIP1, and TAK1. We find that RIP1 is modified by SUMO-1 and ubiquitin in response to DNA damage and demonstrate that modified RIP1 is required for NF-κB activation and tumor cell survival. We show that ATM activates TAK1 in a manner dependent on RIP1 and NEMO. We also reveal TAK1 as a central mediator of the alternative DNA damage response pathway mediated by the p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 (MAPKAP-2) kinases. These findings have translational implications and reveal RIP1 and TAK1 as potential therapeutic targets in chemoresistance. |
| Databáze: | OpenAIRE |
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