Bcl-2 Protein Family Role in Apoptosis

When the cell is not undergoing apoptosis, anti-apoptotic proteins such as Bcl-2 and Bcl-XL sequester Bax and Bak.  When the cell wishes to undergo apoptosis, the anti-apoptotic proteins are sequestered by the BH3-only pro-apoptotic proteins, releasing Bax and Bak, which allow the release of cytochrome C from the mitochondrial membrane, uncoupling the electron transport chain and inducing the activity of caspases.  In healthy cells, p53 is a transcription factor for the pro-apoptotic BH3-only proteins Bik, Bid, PUMA, NOXA, as well as for Bax, the pro-apoptotic protein with BH1, BH2, and BH3 homology and the most downstream member of the Bcl-2 family in the regulation of apoptosis.  Due to the fact that the majority of TP53 mutations present in HGSOC are in its DNA binding region, the transcriptional activation effect of p53 no longer is present for these pro-apoptotic proteins.  The major problem is that many of the BH3-only pro-apoptotic proteins responsible for inhibition of the anti-apoptotic proteins that, when active, inhibit the pro-apoptotic proteins Bax and Bak, do not get transcribed enough without functional p53.