A cytosolic ATM/NEMO/RIP1 complex recruits TAK1 to mediate the NF-kappaB and p38 mitogen-activated protein kinase (MAPK)/MAPK-activated protein 2 responses to DNA damage.
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.
Pubmed ID: 21606198 RIS Download
Animals | Antibiotics, Antineoplastic | Antineoplastic Agents, Phytogenic | Ataxia Telangiectasia Mutated Proteins | Cell Cycle Proteins | Cells, Cultured | DNA Damage | DNA-Binding Proteins | Doxorubicin | Etoposide | GTPase-Activating Proteins | Gene Silencing | Humans | I-kappa B Kinase | Intracellular Signaling Peptides and Proteins | MAP Kinase Kinase Kinases | Mice | Mice, Knockout | Mitogen-Activated Protein Kinase 1 | Multiprotein Complexes | NF-kappa B | Protein-Serine-Threonine Kinases | RNA, Small Interfering | SUMO-1 Protein | Tumor Suppressor Protein p53 | Tumor Suppressor Proteins | Ubiquitin | p38 Mitogen-Activated Protein Kinases