Anti-apoptotic effects

Andrabi, S. A., Sayeed, I., Siemen, D., Wolf, G. Horn, T. F. (2004). Direct inhibition of the mitochondrial permeability transition pore a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J. 18, 869-71. 

This chapter describes the metabohsm of sphingosine and SIP, evidence to support their pro- and anti-apoptotic effects and their proposed sites of action on signaling processes that contribute to apoptosis and proliferation. 

The mechanistic basis of the anti-neoplastic activity of UDCA and the explanation for the significant difference in bioactivity of UDCA compared with DCA despite marked similarity in chemical structure remain unresolved. UDCA administration in healthy volunteers and colorectal adenoma patients has been demonstrated to decrease the proportion of DCA in aqueous phase stool. Therefore, one possible mechanism of the chemopreventative activity of UDCA is reduction of mucosal secondary bile acid exposure. Consistent with this idea, UDCA administration has been demonstrated to reduce the incidence of K-ras mutations and decrease Cox-2 expression in AOM-induced tumors, which is the opposite of the reported effects of DCA in the same model. However, it is clear that exogenous administration of UDCA has direct anti-neoplastic activity on human CRC cells in vitro, either alone or in combination with DCA, including anti-proliferative and anti-apoptotic effects, as well as induction of cell senescence. " ... 

Nitric oxide synthase. The NO synthase (NOS) can generate both pro- and anti-apoptotic effects. The deleterious effects of excessive NO production are well documented in neuronal damage following ischemia and glutamate excitotoxicity (Dawson et al., 1991 Huang et al., 1994). 

It is generally accepted that Bcl-2 family proteins localize to the OMM where they act as gatekeepers of the permeability to cyt c, with Bcl-2 inhibiting the formation of the permeation channels by Bax and/or Bak multimers (Antonsson et al., 2000 Scorrano and Korsmeyer, 2003). The anti-apoptotic effects of Bcl-2 (and Bcl-XL) have been originally interpreted as the result of direct PTP modulation at the OMM. The first indication that the PT could be modulated by Bcl-2 family... 

Under less extreme conditions, DNA-PK plays a central role in repairing double-strand breaks in DNA (Burma and Chen, 2004 Collis et al., 2005). This repair function probably accounts for known anti-apoptotic effects of DNA-PK on embryonic and early postnatal neurons (Chechlacz et al., 2001, Vermuri et al., 2001) and on early postnatal and adult neurons subject to excitotoxicity and oxidative stress (Culmsee et al., 2001 Neema et al., 2005). We will consider later the possibility that these anti-apoptotic effects may be mediated in part by DNA-PK phosphorylation of dysbindin-1 (see Section 2.2.6.53). 

The anti-apoptotic effect of dysbindin-1 is due in part to increased Akt signaling, which is well known for its ability to suppress apoptosis (see Manning and Cantley, 2007). As shown by Numakawa et al. (2004), overexpression of dysbindin-1 in immature cerebrocortical neurons increases phosphorylation of Akt (O Figure 2.2-22a), whereas dysbindin-1 knockdown had the opposite effect ( Figure 2.2-22b). 

The anti-apoptotic effect was significantly reduced when the neurons were treated with a PI3K inhibitor (LY294002) able to decrease Akt phosphorylation (Numakawa et al., 2004). It is unclear how dysbindin-1 is able to activate Akt, though there is a predicted Akt binding site in the NTR of dysbindin-1 enabling a direct feedback for activated Akt (see Figure 2.2-2 and Table 2.2-5). 

It is also unclear what role the predicted DNA-PK site in dysbindin-1 may have in enabling or mediating its anti-apoptotic effect. As explained earlier (see Section 2.2.3.3.1), DNA-PK, which phosphorylates dysbindin-1 (Oyama et al., 2009), helps repair double-strand DNA breaks and suppresses apoptosis in developing and adult neurons (cf., Chechlacz et al., 2001, Culmsee et al., 2001, Vermuri et al., 2001, and Neema et al., 2005). Anti-apoptotic effects of DNA-PK on prenatal neurons (Vermuri et al., 2001) presumably have a major impact on brain development, especially given that the highest levels of DNA-PK are found in fetal tissue (Oka et al., 2000). It will thus be important to test if DNA-PK phosphorylation of nuclear dysbindin-1 in developing neurons contributes to the survival of those cells. 

Plotkin, L.I., Lezcano, V., Thostenson, J., Weinstein, R.S., Manolagas, S.C., and Bellido, T. (2008). Connexin 43 is required for the anti-apoptotic effect of bisphospho-nates on osteocytes and osteoblasts in vivo. J Bone Miner Res 23 1712-1721. 

L. Ma, Anti-apoptotic effects of rosiglitazone in hypcrcholesterolcmic rabbits subjected to myocardial ischemia and reperfusion, Cardiovasc Res 62,135-44 (2004). 

In a second way in which Akt kinase controls apoptosis, Akt kinase directly phosphorylates key regulators of apoptosis. The best-studied example of this type of control involves the Bad protein, which is a proapoptotic member of the Bcl-2 family. The Bad protein is phosphorylated by Akt kinase at Ser residues, and this modification promotes translocation of Bad to the cytosol, where it is found complexed with 14-3-3 proteins. By this mechanism, the pro-apoptotic effect of Bad can be inhibited. The effect on Bad is, however, not universal and is observed only in some cell types. Another pro-apoptotic substrate of Akt kinase is procaspase-9, which is inhibited upon phosphorylation by Akt. Dysregulation of the PI3-kinase/Akt kinase pathway, e. g., by inactivation of the PTEN tumor suppressor, has an anti-apoptotic effect and will favor tumor formation by preventing the death of cells that would be channeled to apoptosis under normal circumstances. 

Lafon-Cazal M, Perez V, Bockaert J et al (2002) Akt mediates the anti-apoptotic effect of NMDA but not that induced by potassium depolarization in cultured cerebellar granule cells. Eur J Neurosci 16 575-583... 

Like virtually all intracellular signaling events, phosphorylation by PT3 kinase is reversible. The relevant phosphatase, termed PTEN phosphatase, has an unusually broad specificity. Although PTEN can remove phosphate groups attached to serine, threonine, and tyrosine residues in proteins, its ability to remove the 3-phosphate from PI 3,4,5-trisphosphate is thought to be its major function in cells. Overexpression of PTEN in cultured mammalian cells promotes apoptosis by reducing the level of PI 3,4,5-trisphosphate and hence the activation and anti-apoptotic effect of protein kinase B. 

---