Apoptotic signaling

For activating pro- and anti-apoptotic signaling, B-cell lymphoma 2 (Bel-2) family proteins are reported to play important roles. Bcl-2 family proteins, Bcl-2, Bcl-xL, and Bcl-w are classified as antiapoptotic proteins, which share four domains BHl, 2, 3, and 4 (Chipuk et al. 2010). Other Bcl-2 family proteins, Bax and Bak, are classified as pro-apoptotic proteins which share multidomain of BHl, 2, and 3 (Chipuk et al. 2010). Also Bid, Bil, Bad, Bim, and Bmf are classified as pro-apoptotic protein, but these proteins share only BH3 domain, thus these are also called BH3-only proteins (Chipuk et al. 2010). 

FIGURE 10.3. Autophagy and apoptosis signaling model. BH3 domain only protein egl-1 bind with Bcl-2/ced-9 protein and activate autophagy protein Beclin and pro-apoptotic protein Apaf-1. 

When egl-1 binds to ced-9 protein, the complex of ced-9 with ced-4 or bec-1 is disrupted and ced-4 and bec-1 is released (Pinan-Lucarre et al. 2012). Free ced-4 activates caspases, which cause neuronal apoptosis (Pinan-Lucarre et al. 2012). Also, free bec-1 is suggested to be cleaved by caspases, and its fragments do not increase autophagy, but increase apoptosis signaling (Wirawan etal. 2010). 

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ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Vlahakis SR, VUlasis-Keever A, Gomez T, Vanegas M, Vlahakis N, Paya CV (2002) G protein-coupled chemokine receptors induce both survival and apoptotic signaling pathways. J Immunol 169 5546-5554... 

Abnormal growth factor signaling pathways lead to increased cell proliferation, suppression of apoptotic signals, and invasion contributing to metastasis. 

Palozza, P., Serini, S., Di Nicuolo, R et al. 2001b. Mitogenic and apoptotic signaling by carotenoids Involvement of a redox mechanism. IUBMB Life 52 77-81. 

Malignant Reed-Sternberg cells overexpress nuclear factor-K B, which is associated with cell proliferation and anti-apoptotic signals. Infections with viral and bacterial pathogens upregulate nuclear factor-K B. Epstein-Barr virus is found in many, but not all, HL tumors. 

The combinatorial approach, which combines a blocker of anti-apoptotic signaling with a stimulator of stress signaling, could prove to be a general approach. 

Huang YL, Shen CK, Luh TY, Yang HC, Hwang KC, Chou CK (1998) Blockage of apoptotic signaling of transforming growth factor-beta in human hepatoma cells by carboxyfullerene. Eur. J. Biochem. 254 38—43. 

Hence, in the present chapter, we addressed the important questionas to how cytochrome c is released from mitochondrial inner membrane by apoptotic signals independently of A Fm dissipation. We have proposed that peroxidation of cardiolipin may result in a discharge of cytochrome c due to a weakening of the interaction between the lipid and the protein. 

R., 1995, Multiple pathways originate at the Fas/APO-1 (CD95) receptor sequential involvement of phosphatidylchohne-specificphosphohpase C and acidic sphingomyehnase in the propagation ofthe apoptotic signal. EMBO J. 14 5859-5868... 

SHP recruitment by the BCR cross-linked FcyRJIb was suggested to attenuate a pro-apoptotic signal initiated by the latter (Ono et al, 1996). 

Caspase-8 activates the effector caspases either directly, or indirectly by promoting the cytochrome c (see p. 140) from mitochondria. Once in the cytoplasm, cytochrome c binds to and activates the protein Apaf-1 (not shown) and thus triggers the caspase cascade. Apoptotic signals can also come from the cell nucleus. If irreparable DNA damage is present, the p53 protein (see p. 394)—the product of a tumor suppressor gene—promotes apoptosis and thus helps eliminate the defective cell. 

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