Survival requires the active inhibition of apoptosis, which is accomplished either by inhibiting caspases or by preventing their activation. The PI3K pathway, activated by many survival factors, leads to the activation of Akt, an important player in survival signaling. Activated Akt inhibits the proapoptotic Bcl-2 family member Bad, directly inhibits caspase-9, and inhibits additional apoptotic pathways linked to FKHR and GSK-3. Many growth factors and cytokines induce anti-apoptotic Bcl-2 family members. The Jaks and Src phosphorylate and activate Stat3, inducing the expression of Bcl-xL and Bcl-2. Erk1/2 and PKC activate p90RSK, which activates CREB and induces the expression of Bcl-xL and Bcl-2. These Bcl-2 family members protect the integrity of mitochondria, preventing cytochrome c release and the subsequent activation of caspase-9. TNF not only induces apoptosis by activating caspase-8 and -10, but can also inhibit apoptosis signaling via NF-kappaB, which induces the expression of IAP, an inhibitor of caspases 3, 7 and 9.
