TAB1 Links MAPK Signaling to the p53 Pathway

Cellular stress promotes p53 stabilization and activation via posttranslational modifications, which are mediated in part by MAPK proteins such as p38α (also known as MAPK14) and modulate the interaction between p53 and its negative regulators MDM2 and MDMX. TGFβ-activated kinase 1 (TAK1, also known as MAP3K7) and its adapter protein TAK1-binding protein (TAB1) have been shown to activate various pathways including NF-κB and MAPK signaling, but a role for these proteins in the regulation of p53 has not been described. Zhu and colleagues found that TAB1 interacted with MDM2 and inhibited its E3 ligase activity in human cancer cells, resulting in decreased p53 degradation. TAB1 silencing in MDM2-depleted cells reduced both the extent of p53 stabilization and induction of p21 that were seen upon knockdown of MDM2 alone, and thereby partially rescued cell-cycle arrest triggered by MDM2 loss. Intriguingly, depletion of TAB1 impaired p53-dependent apoptosis and enhanced cell survival in cells treated with cisplatin but not those treated with other genotoxic drugs, suggesting that TAB1 regulates p53 activation under certain stress conditions. TAB1-mediated regulation of cell death in response to cisplatin was dependent on activation of p38α, which stimulated p53 phosphorylation and selective induction of the proapoptotic p53 target NOXA. In addition, TAB1-induced stabilization and mitochondrial localization of MDMX, which has been implicated in p53-driven intrinsic apoptosis, was also required for cisplatin-triggered cell death. Of note, TAB1 expression was reduced in human ovarian tumor samples and cisplatin-resistant ovarian cancer cells, suggesting that TAB1 loss may contribute to tumor growth and drug resistance. Although additional studies are needed to clarify the role of TAB1 in the response to cisplatin, these findings suggest that TAB1 may function as a tumor suppressor and identify this protein as a link between MAPK signaling and p53 activation.

Zhu Y, Regunath K, Jacq X, Prives C. Cisplatin causes cell death via TAB1 regulation of p53/MDM2/MDMX circuitry. Genes Dev 2013 Aug 9 [Epub ahead of print].