MAPK pathway

Abstract

Oxidative stress activates the MAPK signaling pathway. ERK, JNK, and p38 kinase activation in response to oxidative stress through the production of reactive oxygen species (ROS) can have both prosurvival and proapoptotic effects. ROS-activated PLC-gamma and Src phosphorylate Ras and Raf, both directly and indirectly, which ultimately leads to ERK activation. Activated ERK both positively and negatively regulates ROS levels indirectly via induction of p22phox, which increases ROS production, and activation of Nrf2, which upregulates antioxidants. ROS also activates ASK1 via several mechanisms including relief of ASK1 inhibition by thioredoxin (Trx) and PP2C epsilon, and by activation of PP2B, a positive regulator of ASK1. Activated ASK1 ultimately leads to the activation of JNK and p38. Like ERK, JNK has both prosurvival and proapoptotic roles in response to oxidative stress. Activated JNK can promote cellular survival via the activation of FoxO, which upregulates antioxidant production, and SIRT1, which inhibits p53-dependent transcription. Conversely, activated JNK can promote apoptosis via activities both in the cytoplasm and in the nucleus. In the cytoplasm, JNK positively regulates proapoptotic proteins, such as BIM/BMF and p66SHC, and negatively regulates antiapoptotic proteins, such as Bcl-xL. In the nucleus, JNK activates multiple transcription factors that induce proapoptotic gene expression. p38, once activated, translocates to the nucleus and activates the ATF2 and CREB transcription factors via MSK1/2. ATF2 and CREB subsequently promote apoptosis by inducing the expression of many proapoptotic genes.