Withdrawal symptoms on display: Bcl-2 members under investigation.

The balance between survival and apoptosis of lymphocytes is considered to be regulated by specific signals delivered through cell surface receptors binding either antigen (fragments) or homeostatic cytokines. Expanding lymphocytes must also compete for nutrients. For growth factors and nutrients, recent data indicate how these generic environmental signals couple to members of the apoptosis-regulating Bcl-2 family. The prosurvival molecule Mcl-1 is engaged by lethal BH3-only proteins Puma and Noxa under these circumstances. We propose that Puma and Noxa have specific roles in tipping the balance towards apoptosis after growth factor withdrawal and nutrient shortage, respectively. These complementary mechanisms tune survival in the various niches when lymphocytes compete for resources during selection and expansion.