BCL-2

Detailed Information

Particularly by preventing the death of certain cell types including lymphocytes, the BCL2 gene codes an essential outer mitochondrial membrane protein that is vital in controlling death. Particularly in cases where BCL2 translocates to the immunoglobulin heavy chain locus, the constitutive expression of BCL2 is thought to be rather important for the development of follicular lymphoma. Different splicing of the BCL2 gene produces many transcript variants, therefore adding complexity to its functional range. Because BCL2 interacts with many routes and biological processes, its multifarious character has attracted much interest in both clinical and scientific settings.

Functional Mechanisms of BCL2 Protein

BCL2 protein controls death in many different cell systems, including those depending on lymphohematopoietic and brain cells, employing functional mechanisms. Its main job is to control cell death by changing mitochondrial membrane permeability. BCL2 seems to operate in a feedback loop system including caspases, the death executioners. It blocks the release of cytochrome c from the mitochondria and/or binds to apoptosis-activating factor-1 (APAF-1), therefore reducing caspase activation. Under stress, cellular homeostasis is maintained in great part by this inhibition.

Furthermore, BCL2 suppresses autophagy by interacting with proteins like BECN1 and AMBRA1 in non-starvation circumstances, therefore preventing their autophagic activities. Furthermore, data points to BCL2 possibly reducing inflammation by blocking the activation of the NLRP1 inflammasome, hence influencing CASP1 activation and IL1B output.

Structural Characteristics of BCL2

Comprising 239 amino acids, the BCL2 protein has a molecular weight of around 26 kDa. Three structural domains make up it: the BH4 domain, the BCL domain, and a transmembrane (TM) region. Unique to anti-apoptotic proteins, the BH4 domain (amino acids 7-33) is essential for proper globular BCL2 structure development and folding. Three subdomains—BH1, BH2, and BH3—that produce a hydrophobic groove comprise the BCL domain (amino acids 97-155). By helping pro-apoptotic proteins to attach, these grooves help to neutralize their death-causing action and stop cell death. Amino acids 214–236, the TM region, hooks BCL2 to organelle membranes.

Though it is also expressed in the endoplasmic reticulum and the adjacent nuclear membrane, BCL2 is mostly found in the mitochondria. Its expression is seen in many different kinds of cells; astrocytes, Schwann cells, and T cells especially show high amounts. Recent RNA-seq studies of 95 individuals' samples found that BCL2 gene expression is greatest in the thyroid gland followed by notable expression in the ovaries, adipose tissue, endometrium, and spleen.

The Role of BCL2 in Apoptosis

The most studied kind of programmed cell death, apoptosis, is essential for the growth and development of an organism. The BCL2 family of proteins mostly controls intrinsic (mitochondria-mediated) death, which is essential for which their membrane permeability modulates. Intrinsic death reacts to many intracellular stress signals including protein misfolding, DNA damage, and mitochondrial depolarization.

Most anti-apoptotic proteins—including BCL2—integrate into organelle membranes under non-stress circumstances, binding to pro-apoptotic proteins and therefore suppressing their activity. BH3-only proteins like Bid, Bim, and Puma (activators) turn on when apoptotic signals show up. While other BH3-only proteins, or sensitizers, including Bad, Bik, Bmf, and Noxa bind with great affinity to anti-apoptotic proteins, freeing Bax and Bak from their inhibitory complexes, these proteins may directly activate Bax and Bak. Cytochrome c and other apoptotic components that trigger downstream caspase cascades are released when Bax and Bak oligomerize on the outer mitochondrial membrane causing mitochondrial outer membrane permeabilization (MOMP). This amplification of death signals finally cleavishes hundreds of proteins, leading to cellular death.

Figure 1. Regulation of the intrinsic apoptotic pathway by the BCL-2 protein family. (Kaloni D, et al., 2023)

Clinical Implications of BCL2 Dysregulation

Normal physiological circumstances allow BCL2 to be mostly expressed in rapidly dividing or differentiating cells. Its expression lowers during planned cell death, which releases dead components. But when BCL2 is overexpressed during death, it may seriously interfere with the release of cytochrome c and SMAC, therefore stopping the dying process. Unchecked cellular proliferation brought on by this abnormal overexpression opens the path for cancer formation.

Research on several malignancies, including ovarian cancer, lung cancer, prostate cancer, breast cancer, colorectal cancer, nasopharyngeal carcinoma, and leukemia, has shown BCL2 overexpression. Tumor development, progression, treatment resistance, and low general survival rates are intimately correlated with its overexpression. The consequences of BCL2 in cancer biology emphasize the gene's potential therapeutic target and disease progression biomarker value.

BCL2 in Regenerative Medicine

Research on the purposes of the BCL2 gene has advanced and its uses now go beyond just cancer. Especially in the realm of organ regeneration, the importance of BCL2 has been underlined. Using human induced pluripotent stem cells (iPSCs), a historic study headed by experts from the Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, revealed in 2023 the first successful regeneration of human-like kidneys in pigs. This success marks a major step toward a bioengineering-based worldwide solution for donor organ shortages.

Early research revealed that overexpression of the MYCN and BCL2 genes improved human iPSC survival and competitive advantage in xenogeneic embryos. Researchers effectively produced 4CL/N/B cells displaying improved chimeric capabilities, competitive and proliferative capacity, and boosted survival and differentiation potential inside pig embryos by combining Miguel A. Esteban's team's created 4CL culture method. By use of optimal embryonic compensatory strategies, the researchers produced high-quality rebuilt chimeric embryos fit for organ regeneration under xenogeneic conditions.

BCL2 and Autoimmunity

The development and course of many autoimmune disorders have been linked to the BCL2 protein family. Increased proliferation and immune cell survival resulting from too high expression of certain BCL2 family members might cause ongoing inflammatory and autoimmune reactions. On the other hand, the lack or downregulation of several BCL2 family members might disturb immune cell survival and function, therefore causing immunological dysregulation and maybe leading to autoimmune disorders.

BCL2 in Neurodegenerative Disorders

The BCL2 protein family is linked to neurodegenerative diseases, which include Alzheimer's disease, Parkinson's disease, and Huntington's disease, and defines a spectrum of disorders marked by the slow degeneration of neurons in the central and peripheral nervous systems. Essential for preserving neural life and functional stability in the nervous system, BCL2 proteins serve a crucial anti-apoptotic function. Dysregulation of BCL2 expression or function may cause neuronal death, therefore hastening the course of a disease.