Posttranslational modifications of Bcl2 family members - a potential therapeutic target for human malignancy

Apoptosis is a process that can occur normally, such as during tissue remodeling, embryogenesis or abnormally during certain pathologies, such as cancer (14). The identification of the Bcl2 (5) as well as IAP family members (6) has suggested that excessive inhibition of apoptosis may constitute a common feature of all known human cancers-the ability to influence their onset, progression and outcome. Bcl2 family proteins are frequently regulated by phosphorylation that affects their activity and conformation. The structural analysis of antiapoptotic members of Bcl2 family has contributed to a better understanding of the functional domains including the discovery of an unstructured loop region (LR) near the N-terminus exposed to the cytoplasm. The antiapoptotic members of Bcl2 family such as Bcl2/Bcl-xL/Mcl-1 are phosphorylated on specific serine/threonine residues within this unstructured loop in response to diverse stimuli including treatment with chemotherapeutic taxanes, survival factor addition or chemopreventive agents. In most instances, such phosphorylation has been associated with the loss of their biological function (7-71). The chemoresistant tumors overexpress Bcl2/Bcl-xL/Mcl-1(72). To this end, the apoptosis yielding effect due to phosphorylation of antiapoptotic Bcl2 family members is quite interesting. Phosphorylation-dephosphorylation pathway of these antiapoptotic proteins should be an ideal molecular target for therapy of subpopulation of cancer in which these death repressors are essential prognostic markers. Thus, further gaining the knowledge on the mechanism of inactivation of Bcl2/Bcl-xL/Mcl-1 by phosphorylation might be of paramount importance to therapy for human malignancies in which overexpression of these antiapoptotic proteins plays an essential role.