Inhibition of Apoptosis

Cell survival requires the active inhibition of apoptosis, which is accomplished by inhibiting the expression of pro-apoptotic factors as well as promoting the expression of anti-apoptotic factors. The PI3K pathway, activated by many survival factors, leads to the activation of Akt, an important player in survival signaling. PTEN negatively regulates the PI3K/Akt pathway. Activated Akt phosphorylates and inhibits the pro-apoptotic Bcl-2 family members Bad, Bax, caspase-9, GSK-3, and FoxO1. Many growth factors and cytokines induce anti-apoptotic Bcl-2 family members. The Jaks and Src phosphorylate and activate Stat3, which in turn induces 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-α may activate both pro-apoptotic and anti-apoptotic pathways; TNF-α can induce apoptosis by activating caspase-8 and -10, but can also inhibit apoptosis via NF-κB, which induces the expression of anti-apoptotic genes such as Bcl-2. cIAP1/2 inhibit TNF-α signaling by binding to TRAF2. FLIP inhibits the activation of caspase-8.

Selected Reviews:

• Brumatti G, Salmanidis M, Ekert PG (2010) Crossing paths: interactions between the cell death machinery and growth factor survival signals. Cell. Mol. Life Sci. 67(10), 1619–30.
• Fuchs Y, Steller H (2011) Programmed cell death in animal development and disease. Cell 147(4), 742–58.
• Fulda S, Vucic D (2012) Targeting IAP proteins for therapeutic intervention in cancer. Nat Rev Drug Discov 11(2), 109–24.
• Kaufmann T, Strasser A, Jost PJ (2012) Fas death receptor signalling: roles of Bid and XIAP. Cell Death Differ. 19(1), 42–50.
• Lopez J, Meier P (2010) To fight or die - inhibitor of apoptosis proteins at the crossroad of innate immunity and death. Curr. Opin. Cell Biol. 22(6), 872–81.
• Rong Y, Distelhorst CW (2008) Bcl-2 protein family members: versatile regulators of calcium signaling in cell survival and apoptosis. Annu. Rev. Physiol. 70, 73–91.
• Srinivasula SM, Ashwell JD (2008) IAPs: what's in a name? Mol. Cell 30(2), 123–35.
• Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim. Biophys. Acta 1813(11), 1978–86.

We would like to thank Prof. Junying Yuan, Harvard Medical School, Boston, MA, for reviewing this diagram.

created September 2008

revised November 2012