BCL-2: A Drug Target and Biomarker for B-cell Lymphoma (G596)

NCBI ID: G596

BCL2

BCL-2: A Drug Target and Biomarker for B-cell Lymphoma

BCL-2, also referred to as B-cell lymphoma-2, is a protein that plays a crucial role in determining cell survival or cell death through apoptosis. It is involved in maintaining cellular homeostasis by regulating the balance between pro-apoptotic and anti-apoptotic proteins.

Anti-apoptotic proteins, including BCL-2, BCL-XL, BCL-W, and MCL-1, bind to the pro-apoptotic molecules BID and BIM . This binding prevents the activation of BAX and BAK, which are responsible for initiating mitochondrial outer membrane permeabilization (MOMP) and subsequently leading to apoptosis. By antagonizing the activator and effector molecules, the anti-apoptotic proteins block the apoptotic cascade.

However, cell death signals also activate sensitizer molecules, such as BH3-only proteins like BIM, BID, PUMA, NOXA, and BAD. These sensitizer molecules displace or prevent the anti-apoptotic proteins from binding to BAX and BAK, allowing for cytochrome c release into the cytosol and activation of the caspase cascade, resulting in cell death.

The balance between pro- and anti-apoptotic BCL-2 proteins is essential for maintaining cellular homeostasis. In a prosurvival mode, BAK/BAX interacts with antiapoptotic BCL-2 proteins, thereby preventing the execution of the apoptotic program and allowing cells to survive. In contrast, activation of BAK/BAX can occur under stress or upon receiving upstream signals that act on the BH3-only proteins, leading to apoptosis.

Navitoclax, a potential therapeutic agent, interacts with antiapoptotic BCL-2 family proteins to potentiate apoptotic activity. CS055, another compound, induces DNA double-strand break accumulation and alters the balance of pro-apoptotic and anti-apoptotic Bcl-2 proteins. This alteration, along with the inhibition of Bcl-2 by ABT-199 and downregulation of Mcl-1 and Bcl-xL by CS055, can induce apoptosis and potentially overcome resistance to ABT-199 in acute myeloid leukemia (AML) cells.

In summary, BCL-2 proteins play a critical role in determining cell survival or cell death through the regulation of apoptosis. Anti-apoptotic BCL-2 proteins bind to pro-apoptotic molecules, preventing the initiation of apoptosis. However, sensitizer molecules can displace or prevent the binding of anti-apoptotic proteins, leading to cell death. The balance between pro- and anti-apoptotic BCL-2 proteins is crucial for maintaining cellular homeostasis. Therapeutic agents, such as navitoclax and CS055, interact with BCL-2 family proteins to potentiate apoptosis and potentially overcome resistance in certain cancers.
Based on the provided context information, the BCL-2 family of proteins plays a critical role in regulating apoptosis, the programmed cell death process. These proteins can be classified as anti-apoptotic (pro-survival) or pro-apoptotic (pro-death), and they interact with each other through binding selectivity profiles. Pro-apoptotic proteins can initiate apoptosis by various mechanisms, such as activating effector proteins, promoting their insertion into mitochondrial membranes, and preventing anti-apoptotic proteins from sequestering pro-apoptotic effectors.

In the context of cancer treatment, small-molecule BH3 mimetics like venetoclax have been designed to bind competitively to anti-apoptotic proteins, liberating pro-apoptotic proteins and triggering apoptosis in cancer cells. These BH3 mimetics have shown selective cytotoxic and antiviral activities. Furthermore, melatonin treatment has been found to induce mitochondrial-mediated cell death in cancer cells by reducing the mitochondrial electron transport chain, generating reactive oxygen species, down-regulating BCL-2, and releasing AIF (apoptosis-inducing factor).

The expression levels of BCL-2 family genes, specifically the BCL2/BCL2L1 ratio, have been found to correlate with sensitivity to BCL2 inhibitors like venetoclax in multiple myeloma (MM) and primary plasma cell leukemia (pPCL). The presence of the t(11;14) translocation has been associated with higher expression levels of BCL2 family genes in MM and pPCL, which may contribute to increased sensitivity to BCL2 inhibitors.

BH3-only proteins can play a role in apoptosis by interacting with anti-apoptotic BCL-2 family members. However, the requirement of BH3-only proteins in apoptosis regulated by both BCL-XL and MCL-1 remains unclear, as the neutralization of anti-apoptotic proteins with BH3 mimetics can still induce apoptosis in the absence of all eight BH3-only proteins. Other BH3-domain containing proteins not classified as the key BH3-only members may interact with BCL-XL and MCL-1 and contribute to apoptosis.

Overall, the BCL-2 family of proteins and their interactions play a crucial role in regulating apoptosis, and targeting these proteins or their interactions with BH3 mimetics holds promise for cancer treatment. Different BCL-2 inhibitors and melatonin have shown cytotoxic and antiviral activities and can induce selective apoptosis in cancer cells. The expression levels of BCL2 family genes, particularly the BCL2/BCL2L1 ratio, may serve as predictive markers for the sensitivity to BCL2 inhibitors. However, the exact role of BH3-only proteins in apoptosis and the involvement of other BH3-domain containing proteins require further investigation .

Protein Name: BCL2 Apoptosis Regulator

Functions: Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells (PubMed:1508712, PubMed:8183370). Regulates cell death by controlling the mitochondrial membrane permeability (PubMed:11368354). Appears to function in a feedback loop system with caspases (PubMed:11368354). Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1) (PubMed:11368354). Also acts as an inhibitor of autophagy: interacts with BECN1 and AMBRA1 during non-starvation conditions and inhibits their autophagy function (PubMed:18570871, PubMed:21358617, PubMed:20889974). May attenuate inflammation by impairing NLRP1-inflammasome activation, hence CASP1 activation and IL1B release (PubMed:17418785)

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