INTRINSIC PATHWAY OF APOPTOSIS AND ITS REGULATION BY BCL2 PROTEINS

 BCL2 PROTEINS REGULATES INTRINSIC PATHWAY OF APOPTOSIS

                                                                                 -EISHIKA DAS

In Intrinsic apoptotic pathway, mitochondrion plays a central role by releasing cytochrome C. The defining event during intrinsic apoptotic pathway Is mitochondrial outer membrane permeabilization or MOMP.

Following MOMP, cytochrome c, are released into the cytosol. Once in the cytoplasm, cytochrome c binds to adaptor protein APAF1.This interaction leads to hydrolysis of the bound dATP to dADP and a change in the conformation of APAF-1. APAF-1 assembles into a heptameric complex, the apoptosome. The APAF-1 proteins in the apoptosome then recruit initiator procaspase-9. The incorporation of procaspase-9 into the apoptosome triggers the auto-activating cleavage of procaspase-9 into caspase-9. Caspase-9, in turn, cleaves procaspase-3 to generate caspase-3, which cleaves targets that cause apoptosis of the cell.

The intrinsic apoptotic pathway is regulated by the BCL-2 family (BCL-2 stands for B-cell lymphoma/leukemia-2 gene) of proteins. This family of proteins comprise both anti-apoptotic members and pro-apoptotic members. Anti-

apoptotic members like BCL-2 itself, BCL-X and BCL-B inhibit apoptosis whereas pro-apoptotic members such as BAX, BAD, BIK promote apoptosis.

The pro-apoptotic BCL-2 proteins consist of two subfamilies - the BH123 proteins and the BH3-only proteins. The main BH123 proteins are BAX and BAK. Important members of the BH3-only proteins are BID, BIM, BIK, BAD, PUMA and NOXA. When an apoptotic stimulus triggers the intrinsic pathway, the pro-apoptotic BH123 proteins-

BAX and BAK - promotes MOMP and the release of cytochrome c and other intermembrane proteins by an unknown mechanism. BH3-only proteins, which are induced transcriptionally or post-translationally by cytotoxic stress signals, carry out their pro-apoptotic function by two mechanisms- neutralization of the anti-apoptotic BCL-2 family

proteins and direct activation of the pro-apoptotic effectors BAX and BAK. BH3-only proteins provide the crucial link between apoptotic stimuli and the intrinsic pathway of apoptosis, with different stimuli activating different BH3-only

proteins. For example, in response to DNA damage that cannot be repaired, p53 protein accumulates and activates the transcription of genes that encode the BH3-only proteins PUMA and NOXA.