The Bcl-2 Family consists of apoptosis regulator Bcl-2 and its homologues. These proteins govern mitochondrial outer membrane permeabilization (MOMP) and can be either pro-apoptotic (Bax, BAD, Bak and Bok among others) or anti-apoptotic (including Bcl-2 proper, Bcl-xL, and Bcl-w, among an assortment of others). There are a total of 25 genes in the Bcl-2 family known to date. These proteins are known as an important gatekeeper to the apoptotic response. This group of structurally related proteins comprises pro-apoptotic and anti-apoptotic members that interact with one another.
According to the function of BCL-2 family, it can be divided into proapoptotic BCL-2 protein and anti-apoptotic BCL-2 protein. Most cells simultaneously express many kinds of apoptotic and anti-apoptotic BCL-2 proteins, which can control cell death by regulating their interaction. Anti-apoptotic BCL-2 protein contains four homologous domains (BH1/4), which are usually integrated into OMM and distributed on the cellular sol and endoplasmic omentum. Antiapoptotic BCL-2 protein maintains the integrity of OMM mainly through direct inhibition of apoptotic BCL-2 protein. Apoptosis promoting BCL-2 protein can be classified into effector protein and BH3 protein (BH3-only protein). There are two kinds of effector proteins including BCL-2 antidestructible protein (BAK) and BCL-2 associated x protein (BAX). BAX and BAK are activated in OMM oligodegenerin lipid pore, thus promoting MOMP.
BH3-only protein is the most important way for cells to deal with external pressure. The low homology between BH3-only protein and BH3-only protein may be the reason that cells can regulate their functions through different mechanisms. When apoptotic signal occurs, BCL-2 protein with multiple domains can regulate and function by changing stability or interacting with other family members. There is a large, disordered ring structure between N terminal and C terminal of BID protein, which has inhibitory function. BID protein embodies its apoptotic function through its unique mechanism that involves a series of proteolytic cleavages of this ring structure.
BCL-2 Family plays a significant role in controlling the division, fusion and fragmentation of mitochondria. Mitochondria undergo a process of division and integration to produce interlinked tubular networks. Therefore, mitochondria are a dynamic organelle. DRP-1 is a soluble molecule that promotes mitochondrial division when recruited to mitochondria. Mitochondrial fusion is controlled by three major GTP enzymes, which suggests that BCL-2 is closely related to mitochondrial homeostasis.
Meanwhile, BCL-2 Family regulate endoplasmic reticulum calcium levels and calcium signal generation and help mitochondria and endoplasmic reticulum to maintain their normal metabolic function. It regulates the interaction between mitochondrial endoplasmic reticulum by affecting the storage and release of calcium ions in endoplasmic reticulum. BCL-2 family affects the storage and release of calcium ions in endoplasmic reticulum through many mechanisms. Thus, the sensitivity of cells to apoptotic stimulation is affected. Calcium ions entering the endoplasmic reticulum are regulated by calcium kinase in the sarcoplasmic reticulum and endoplasmic reticulum. The release of calcium ion is regulated by IP3R (1,4,5-Triphosphoinositide receptor). BCL-2 protein located in endoplasmic reticulum can directly inhibit the activity of IP3R and decrease the activity of IP3R.
BCL-2 family is involved in many diseases, especially cancer. At present, many scholars hope to regulate BCL-2 family with drugs, so as to treat cancer with a single drug or multiple drugs. At present, the most effective and prevalent therapeutic mechanism is the over-expression of anti-apoptotic family members, such as increasing the level of BCL-2 family protein in human malignant tumors. Recent studies have shown that tumor cells contain high levels of anti-apoptotic BCL-2 family proteins to sustain their survival. Therefore, the anti-apoptosis in tumor is inhibited by increasing the integrity of other components in the apoptotic pathway and enhancing the sensitivity of the BCL-2 family members. And proteins can induce spontaneous apoptosis of tumor cells.