Bcl-2 family proteins, beyond the veil

Apoptosis is an important part of both health and disease and is often regulated by the BCL-2 family of proteins. These proteins are either pro- or anti-apoptotic, existing in a delicate balance during homeostasis. They are best known for their role in regulating the activation of caspases and the execution of a cell in response to a variety of stimuli. However, it is often forgotten that these BCL-2 family proteins also have important roles to play in cell maintenance that are not associated with apoptosis. These include roles in regulating processes such as cell cycle progression, mitochondrial function, autophagy, intracellular calcium concentration, glucose and lipid metabolism, and the unfolded protein response. In addition to these established alternate functions, further discoveries are being made that have potential therapeutic benefits in diseases such as cancer. BOK, a BCL-2 family protein thought comparable to multidomain pro-apoptotic proteins BAX and BAK, has recently been identified as a key player in metabolism of and resistance to the commonly used chemotherapeutic 5-FU. As a result of such findings, which could see the potential use of BOK as a biomarker for 5-FU sensitivity or mimetic molecules as a resensitization strategy, new targets and mechanisms of pathology may arise from further investigation into the realm of alternate functions of BCL-2 family proteins.