Beibei Cai

Project title: P38 MAP Kinase Pathway Regulates Apoptosis Through Phosphorylation and Up-regulation of bimEL

Degree: PhD | Program: Environmental Toxicology (Tox) | Project type: Thesis/Dissertation
Completed in: 2008 | Faculty advisor: Zhengui Xia


The mitogen activated protein kinase (MAP kinase) p38 plays a critical role in many cellular functions and has been shown to be activated by many environmental and pharmaceutical agents. p38 has been extensively studied for its role in stress responses including apoptosis. However, the molecular mechanisms underlying p38 mediated apoptosis are not completely understood. Here we show that in arsenite-induced apoptosis, p38 mediates apoptosis through regulating a B cell luckemia-2 (Bcl-2) family protein Bcl-2 interactive mediator of cell death (Bim).

Our data showed that p38 can directly phosphorylate Bim extra long (EL) isofom at serine 65, an activating site which is required for the pro-apoptotic activity of BimEL. We determined a novel mechanism by which p38 activation lead to the induction of apoptosis. This is the first evidence that p38 MAP kinase regulates apoptosis by directly phosphorylating and regulating the activities of a Bcl-2 family protein. We also provided evidence that p38 activation and p38-induced apoptosis may be a common mechanism underlying oxidative stress toxicity. Mechanisms responsible for arsenite-induced peripheral neuropathy have not been elucidated. Results from this study may suggest p38 activation, p38 phosphorylation of BimEL, and subsequent induction of apoptosis as an underlying mechanism.

Besides the phosphorylation of BimEL, We discovered that p38 also regulates Bim at the transcriptional level. We identified p38 as an upstream kinase that facilitates the nuclear translocation and therefore the activation of the transcription factor FOXO3a. Our data showed that p38 inhibition leads to an inactivating phosphorylation of FOXO3a, which may be attributed to cross-talk of p38 with other kinase pathways. The p38-FOXO3a pathway mediated transcriptional activation of Bim in addition to the phosphorylation of Bim, thus establishing a two-level model of p38 regulating on Bim.