The Bcl2 family proteins regulate and mediate the mitochondrial outer membrane permeabilization, a crucial event in the mitochondrial pathway of apoptosis in vertebrates.
The regulation of apoptosis is governed largely by interactions between the pro-survival and pro-death members of the Bcl2 protein family.
Some members of this family (e.g., Bax, Bak, and Bid: pro-apoptotic protines) promote apoptosis, while others such as BCL2, BCL2L1, BCL2L2 (anti-apoptotic protines)work against programmed cell death.
The BCL2 family proteins are characterized by regions of specific sequence homology named as BCL2 homology (BH) motifs that number from 1 to 4 and are critical for function.
Especially a helical BH3 motif of pro-apoptotic proteins occupy and form strong interactions with hydrophobic groove of anti-apoptotic BCL2 family proteins which leads to the activation of the essential death mediators Bax and Bak, thereby committing cells to apoptosis
p53 induces apoptosis by target gene regulation and transcription-independent signaling.
A fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis.
Evidence that p53 translocation to the mitochondria occurs in vivo in irradiatedthymocytes was shown.
Further, p53 can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BCL2L1, resulting in cytochrome c release.
p53 binds to BCL2L1 via its DNA binding domain.
Tumor-derived transactivation-deficient mutants of p53 concomitantly lose the ability to interact with BCL2L1 and promote cytochrome c release.
Fraction of induced p53 translocates to the mitochondria of apoptosing tumor cells. Targeting p53 to mitochondria is sufficient to launch apoptosis.
p53 protein can directly induce permeabilization of the outer mitochondrial membrane by forming complexes with the protective BCL2L1 and BCL2 proteins, resulting in cytochrome c release.
In other hand, cytosolic localization of endogenous p53 was necessary and sufficient for apoptosis. p53 directly activated the pro-apoptotic BCL2 protein Bax in the absence of other proteins to permeabilize mitochondria and engage the apoptotic program.
Binding of BCL2 or BCL2L1 to TP53 therefore antagonizes the activation of BAX via binding to TP53. Like this BCL2 and BCL2L1 also perform their anti-apoptotic effect.
BCL2-XL*:p53*@Mitochondrial outer membrane
Participates in complexes:
In compartment: Mitochondria
In compartment: Mitochondrial outer membrane
Participates in reactions:
As Reactant or Product:
- BCL2-XL*@Mitochondrial outer membrane + p53*|S15_unk@Cytoplasm → BCL2-XL*:p53*@Mitochondrial outer membrane
- BCL2-XL*@Mitochondria + p53*@Mitochondria → BCL2-XL*:p53*@Mitochondria