Phosphorylation of Bcl2 and regulation of apoptosis

Members of the Bcl2 family of proteins are important regulators of programm ed cell death pathways with individual members that can suppress (eg Bcl2, Bcl2-X-L) or promote (eg Bax, Bad) apoptosis. While the mechanism(s) of Bcl 2's anti-apoptotic function is not yet clear, introduction of Bcl2 into mos t eukaryotic cell types will protect the recipient cell from a wide variety of stress applications that lead to cell death. There are, however, physio logic situations in which Bcl2 expression apparently fails to protect cells from apoptosis (eg negative selection of thymocytes). Further, Bcl2 expres sion in patient tumor samples does not consistently correlate with a worse outcome or resistance to anticancer therapies. For example, patient respons e and survival following chemotherapy is independent of Bcl2 expression at least for pediatric patients with ALL. These findings indicate that simple expression of Bcl2 may not be enough to functionally protect cells from apo ptosis, The finding that Bcl2 is post-translationally modified by phosphory lation suggests another level of regulation of function. Recent studies hav e shown that agonist-activated phosphorylation of Bcl2 at serine 70 (single site phosphorylation), a site within the flexible loop domain (FLD), is re quired for Bcl2's full and potent anti-apoptotic function, at least in muri ne IL-3-dependent myeloid cell lines. Several protein kinases have now been demonstrated to be physiologic Bcl2 kinases indicating the importance of t his post-translational modification. Since Bcl2 phosphorylation has been fo und to be a dynamic process involving both a Bcl2 kinase(s) and phosphatase (s), a mechanism exists to rapidly and reversibly regulate Bcl2's activity and affect cell viability. In addition, multisite Bcl2 phosphorylation indu ced by anti-mitotic drugs like paclitaxel may inhibit Bcl2 indicating the p otential wide range of functional consequences that this post-translational modification may have on function. While post-translational mechanisms oth er than phosphorylation may also regulate Bcl2's function (eg ubiquitinatio n), this review will focus on the regulatory role for phosphorylation and d iscuss its potential clinical ramifications.