Regulation of Bim in Health and Disease

Following exposure to a pro-apoptotic stimulus, a sudden intracellular rise in free activated Bim molecules (e.g., by increased transcription and/or translation, increased alternative splicing in favor of BimS, and/or release of Bim from sequestered intracellular storages as a result of phosphorylation) initiates the intrinsic mitochondrial apoptotic pathway. Bim induces apoptosis by directly activating Bax and Bak, or indirectly by interacting with the anti-apoptotic proteins Bcl-2, Bcl-xL and Mcl-1, leading to the release and mitochondrial transfer of Bax and Bak. Under normal conditions, Bak is hold in check by Mcl-1, VDAC2 and Bcl-xL. Bax/Bak oligomerization in the mitochondrial outer membrane results in dissipation of the mitochondrial outer membrane potential (Δψm) and release of the apoptogenic proteins cytochrome C (CytoC), Smac/DIABLO and HtrA2 into the cytosol. Cytochrome C activates Apoptotic protease activating factor 1 (Apaf-1) that facilitates the formation of the apoptosome where caspase 9 is activated to initiate the apoptotic cascade concluded with the activation of caspase 3. Smac/DIABLO antagonizes the anti-apoptotic function of Inhibitors of apoptosis protein (IAPs) such as XIAP, cIAP1 and cIAP2, thereby enhancing apoptosis induction by cytochrome C.

Publication

Regulation of Bim in Health and Disease. (2015) Ronit Vogt Sionov, et al. Oncotarget. 2015 Sep 15;6(27):23058-23134. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions