Bcl-2

By Jamshed Arslan, Pharm D, PhD

By Jamshed Arslan Pharm.D.

By Christina Towers, PhD.

Cell death/recycling pathways such as apoptosis, necroptosis, and autophagy are an integral part of the growth, development, homeostasis as well as the pathophysiology in the life of living organisms. These signaling pathways are highly regulated and some of their key regulatory targets are discussed below.

Apoptosis

Apoptosis, programmed cell death, is primarily characterized by the activation of caspases which further regulate the mass cleavage of proteins and DNA. Some of major the proteins responsible for various apoptotic events are:

The process of autophagy, or lysosome-mediated degradation of damaged proteins and organelles in the cytosol, is a vital cellular process that acts as a quality control mechanism for proteins and organelles. The misregulation of autophagy can lead to an imbalance of cellular homeostasis and the subsequent development of disease.  Therefore, the study of autophagy is at the forefront of neuroscience and cancer research, among others.

Similar to other cell processes, the balance between cell survival and cell death is an important equilibrium that when altered expression of genes can lead to a variety of disease.

The c-Jun N-terminal kinase (JNK) family is a group of regulatory kinases with important functions in cell morphogenesis, inflammation, differentiation, and cell death (1). Aberrant activation of JNK family proteins in cancers has led to interest in small molecule JNK inhibitors as a therapeutic strategy (1). JNK1, also known as MAPK8, is expressed in most tissues and is involved in transduction of extracellular signals such as growth factors or cytokines though a phosphorylation cascade to elicit diverse intracellular responses (1).

p53 is a tumor suppressor that has a central role in regulating cell cycle arrest, DNA repair, and apoptosis. p53 is widely studied for its role in cancer and is mutated or altered in more than half of all cancers (1). This widespread role in tumorigenesis has made p53 one of the most highly studied proteins and a target for anti-cancer therapeutics. Normally, p53 allows cells to sense and respond to cellular stress such as DNA damage or hypoxia (2). In response to these signals, p53 is activated through post-translational modification and protein stabilization.

B-cell lymphoma 2 (Bcl-2) protein is an oncogene that normally acts as an apoptotic inhibitor and localizes to the mitochondrial membrane where it prevents the release of cytochrome c. The Bcl-2 protein family consists of over 20 proteins each containing at least one Bcl-2 homology (BH) domains and have either proapoptic or antiapoptotic activities.

The Beclin 1 protein is a central regulator of autophagy in mammalian cells. Autophagy is an essential process used to maintain cellular homeostasis by degrading and recycling cellular components such as damaged or worn out organelles and macromolecules. Autophagy is also activated in response to cellular stresses such as nutrient starvation or intracellular pathogens and can protect the cell from programmed cell death.