BRAIN CHEMOTHERAPY FROM THE BENCH TO THE CLINIC: TARGETING NEURONAL SURVIVAL WITH SMALL MOLECULE INHIBITORS OF APOPTOSIS

Paul C. Chin and Santosh R. D'Mello

The Molecular and Cell Biology Department, FO 3.1, The University of Texas at Dallas, P.O. Box 830688, Richardson, Texas 75083-0688

FIGURES

Figure 1. Caspase activation pathway. The figure delineates the extrinsic and intrinsic pathways of caspase activation. Activation of initiator caspases either by extracellular signals or by internal signals leads to the activation of effector caspases and eventual cell death. AIF, apoptosis-inducing factor; cyto. c, cytochrome c; IAP, inhibitor of apoptosis protein; tBid, truncated Bid; PCD, programmed cell death. For details see text.

Figure 2. Stress-activated MAP kinase pathways. JNK and p38 MAPK are members of the stress-activated MAP kinase (MAPK) pathways. They are dually phosphorylated on a tripeptide motif (Thr-Xaa-Tyr) by a MAP kinase kinase (MAPKK). The MAPKK are activated by a group of MAP kinase kinase kinases (MAPKKK). ASK-1, apoptosis-signal-regulating kinase-1; ATF2, activating transcription factor 2; Ets-1, ets-like-1; JNK, c-Jun NH₂-terminal kinase; MEF2C, myocyte enhancer factor 2C; MKK3/4/6/7, mitogen-activated protein kinase kinase 3/4/6/7; MLK-3, mixed lineage kinase-3; NFAT, nuclear factor of activated T cells; TAK-1, transforming growth factor-b -activated kinase-1; TCFs, ternary complex factors.

Figure 3. The cell cycle and its regulation by CDKs. In normally cycling cells, the cell cycle is composed of four main stages (G1, S, G2, and M) under the direction of cyclin dependent kinases (CDKs). Increasing evidence supports that abortive reentry into the cell cycle by post-mitotic neurons activates programmed cell death machinery.

Figure 4. PI3-K/Akt pathway. Growth factors bind to receptor tyrosine kinases and initiate signaling that leads to the activation of Akt. Once activated, Akt can regulate a diverse array of molecules by phosphorylation. Molecules in green are pro-survival molecules that are activated by Akt, and molecules in red are pro-apoptotic molecules that are inactivated by Akt. CREB, cAMP response element-binding protein; FKHR, Forkhead; GSK3, glycogen synthase kinase 3; IKK, inhibitory k B kinase; IRS, insulin receptor substrate; PDK, phosphoinositide-dependent protein kinase; PI3-K, phosphoinositide 3-kinase.

Figure 5. The Raf-MEK-ERK kinase cascade. Activation of receptor tyrosine kinases leads to recruitment of adaptor proteins Shc and GRB. GRB recruits the GTP exchange factor SOS which activates Ras. Ras activation leads to Raf activation in a series of complex changes in phosphorylation on multiple residues, protein-protein interactions, and protein-lipid interactions. Activated Raf, in turn, activates MEK. MEK phosphorylates the MAP kinase ERK on two residues resulting in activation. In certain populations of neurons, activation of ERK leads to activation of the pro-survival molecule CREB and inactivation of the proapoptotic Bcl-2 protein Bad. ERK, extracellular-signal-regulated kinase; Grb2, growth-factor-receptor-binding protein 2; SOS, son of sevenless.