Regulation of Apoptosis

See also factors which regulate the cell cycle

Bcl-2: Bcl2 and related family members, including BclXS, BclXL, Bad, and Bax, influence apoptosis by regulating the intracellular signals that induce apoptosis. In humans, more than 20 members have been identified, including proteins which suppress and proteins which promote apoptosis. The pro-survival factors include Bcl-2, Bcl-w, and Bcl-X_L. The pro-apoptotic factors include Bax, Bad, Bcl-Xs, and Bak.

Bcl-2 proteins localize or translocate to the mitochondrial membrane and modulate apoptosis by permeabilization of membrane, leading to release of some molecules or the stabilization of barrier function. Several family members like anti-apoptotic Bcl-2 and Bcl-X_L contain a COOH-terminal hydrophobic membrane anchor domain that may target them to various intracellular membranes, including mitochondrial membranes, endoplasmic reticulum, and perinuclear membrane. Mitochondrial Bcl-2 may exert its antiapoptotic function by inhibiting the apoptosis-associated mitochondrial changes, whereas Bcl-2 localized to the ER may contribute to the regulation of apoptosis by inhibiting calcium fluxes and maintaining calcium homeostasis. 

Because members of the Bcl2 family are principally localized within mitochondra, their influence may be greatest in forms of apoptosis that are associated with mitochondrial activation. Thus, Bcl2 overexpression may not inhibit death receptor initiated apoptosis in cells with a type 1 (mitochondria independent) Fas pathway, but it may block Fas-intiated death in type 2 (mitochondria-dependent) cells.

Pro-apototic members of Bcl-2:

Pro-apototic members like Bax exhibit considerable sequence homology with Bcl-2 but others like Bad, Bik, Blk, Hrk, Bid, Bim share only the short (9-16 residue) BH3 domain with the Bcl-2 family. This domain allows them to bind to the prosurvival Bcl-2 like molecules and neutralize their function.

Bid, a pro-apoptotic member of the family is a target for proteolytic cleavage by caspase 8 and granzyme B. Activated caspase 8 cleaves Bid at Asp59 to trigger translocation from the cytosol to the mitochondria where it promotes cytochrome c release.

Bax homodimers by heterodimerizing with the Bax protein to prevent apoptosis.

Bax:  is a Bcl-2 protein family member. Bax homodimerizes or heterodimerizes with Bcl2 or Bcl-X_L. These intereactions have been shown to determine the susceptibility of a cell to a death signal. Decreased Bax mRNA levels, as a result of  catechin EGGG treatment (at low concentrations), may contribute to an increase in the ratio of Bcl-2 or Bcl-X_L to Bax, thus suggesting potential neuroprotective/antiapoptotic features of EGCG.

Bak: is a Bcl-2 protein family member. NF-kB activation upregulates the Bak sequestering proteins Bcl-x and Bcl-2.

Bim is a Bcl-2 protein family member that shares only the BH3 domain with this family.

Inhibitors of Apoptosis (IAPs)

c-FLIP (FLICE-like inhibitory protein) inhibits apoptosis by binding to FADD and thus prevents the activation of caspase 8.

 Bcl-2 Prosurival Members

• Bcl-2 is a member of the Bcl-2 family, itself and promotes cell survival.

• bcl-x is a member of the bcl2 gene family, which may regulate programmed cell death. bcl-x can be alternatively spliced to produce two protein isoforms (Bcl-X_L) and (Bcl-Xs), one of which Bcl-X_L inhibits apoptosis and thus is a pro-survival member.

IAPs or Inhibitor of apoptosis proteins drectly inhibit the activity of specific subsets of caspases. The BIR domain, a 70 residue conserved domain which exists in the members of the IAP fmaily, is essential for the anti-apoptotic proterties of the IAPs.

• XIAP has three BIR domains. It binds directly and inhibits caspases 3, 9 and 7.   (cellular FLICE-like inhibitory protein) inhibits apoptosis by bindign to FADD and thus prevents the activation of caspase 8.

• XAF-1: (X-linked inhibitor of apoptosis associated factor-1) was discovered in a yeast two- hybrid studies as an XIAP interating protein. SAF-1 is a novel IFN stimulated gene.

Compounds affecting Apoptosis:

EGCG: At low concentrations EGCG is more often known for its neuroprotective properties. At higher concentrations EGCG is more often known for its anti-tumorigenic/pro-apoptotic properties. The cell death promotion and increased expression of pro-apoptotic and cell cycle regulatory linked genes, induced by a high EGCG contrentration (50 uM), has been found to correlate with reduced incidence of certain cancers. EGCG was shown to induce apoptosis of neck squamous cell carcinoma cells and to cause a decrease in phosphorylated ERK1/2, Bcl-2 and Bcl-X_L proteins, an increase in Box and activation of caspase 9. High EGCG concentration also reportedly decreased ERK1/2 activation and increased JNK.