Apoptosis and Cellular Signaling Pathways

Signal transduction by the Fas-related TNF receptor is of a more complex nature and can mediate both proapoptotic and antiapoptotic signals. In the normal situation, binding of TNF to its receptor initiates a signal chain that activates a MAPK pathway and creates a signal for c-Jim expression. In addition, the IxB-NFxB pathway may be activated. Both NFkB and c-Jim have an antiapoptotic and proliferation-promoting effect. 

In certain situations, e.g., inhibition of protein biosynthesis, TNF receptor activation has a proapoptotic effect, however, in that caspases are activated and cell death is initiated. 

PI3-kinase (see 6.6) can mediate antiapoptotic signals, in addition to growth-promoting signals (Fig. 14.9). The antiapoptotic signal conduction starts at PI3-kinase to Akt kinase, which is activated by the messenger substance PtdInsPs formed by PI3-kinase. The Bad protein has been identified as a substrate of Akt kinase. The Bad protein is a proapoptotic member of the Bcl-2 family. It is phosphorylated by Akt kinase at several Ser residues and its proapoptotic effect is thus inhibited (Datta et al., 1997). Experimental evidence exists that the 14-3-3 proteins are involved in this inhibition these bind to phosphoserine residues of Bad protein and thus inactivate its proapoptotic fim-ction. 

The p53 protein is at the center of apoptotic signaling pathways initiated by DNA damage and defects in the course of the cell cycle. Depending on cell type, p53-induced apoptosis either requires transcriptional activation (Polyak et al., 1997) or occurs without new RNA and protein synthesis (see Fig. 14.10). 

An important transcriptional target of the p53 protein that can induce apoptosis is the bax gene. The Bax protein belongs to the family of Bcl-2 proteins (see 15.3.2) and has a proapototic effect. There is speculation that the p53-induced increase in Bax concentration leads to formation of ion pores in mitochondria and that cytochrome c is released into the cytosol via these pores. Cytochrome c then functions as a cofactor which, together with Apafl protein, activates procaspase 8 and initiates the apoptotic program. 

---

We begin our discourse on cell death with a summary of the tools and the components of the machinery that carry out the CD programme. We shall see that, despite a bewildering variety of new names, regulation of the apoptosis pathways has basic features in common with other cellular signalling pathways. 

Tet-On Antisense COX-2 Clones. The lack of correlation between the 50% inhibitory concentrations (IC q) values for COX-2 inhibition and the apoptosis-inducing effects of the selective COX-2 inhibitors highlighted in Table 1, as well as the novel cellular targets identified for celecoxib within the Akt and ERK2 signaling pathways and [Ca Ji regulatory machinery in prostate cancer cells, support the idea that COX-2-independent mechanisms play a role in the apoptotic effects of COX-2 inhibitors. 

More recently, studies begin to emphasize the bioactivities of flavonoids through modulating several cellular signaling pathways involved in cell apoptosis, proliferation, survival, and inflammatory responses. 

While multiple signaling pathways are implicated in mediating the proliferative effects of CXCL12, only Akt activation, p38 activation, and suppression of cAMP levels have been shown to influence the survival response. Vlahakis et al. (2002) demonstrated that CXCL12 regulates survival in CD4-t T lymphocytes via the balance of pro-survival Akt activation and pro-apoptotic p38 activation. Whether the cellular response to CXCL12 was survival or apoptosis depended on coincident activation of these pathways by other factors. 

---