The BCL-2 family constitutes a crucial checkpoint in the cell death pathway. BAD is a unique member of this family with a conserved BH3 domain that is required for heterodimerization with anti-apoptotic BCL-2 and BCL-XL and for its proapoptotic function. The function of BAD is regulated by phosphorylation mediated through signal transduction pathways. In the presence of a survival factor IL-3, BAD is phosphorylated on two serine residues (Serines 112 and 136) and is unable to associate with BCL-XL. Instead, it remains sequestered by the cytosolic phosphoserine binding protein 14-3-3. However, following IL-3 withdrawal, BAD undergoes rapid dephosphorylation and in this form is able to dimerize with BCL-XL. Substitution of serine phosphorylation sites to alanine further enhanced BAD's proapoptotic function. Furthermore, BAD will undergo a caspase-dependent cleavage in response to a death stimulus (TNFalpha and cycloheximide). Therefore, BAD provides an ideal model system to study the connection between the upstream signaling pathways (survival or death stimuli) and the intrinsic cell death machinery. The proapoptotic function of BAD also suggests its potential importance in normal development and tumorigenesis. In this context, I propose the following specific aims: (l) Identify the kinase(s) responsible for BAD phosphorylation; (2) Investigate the role of caspase-dependent cleavage of BAD; (3) Define the role of BAD in normal development and tumorigenesis.
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