Apoptotic signaling pathways

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... 

Based on the triggering stimulus and the nature of the components involved, at least two apoptotic signaling pathways can be differentiated that lead to activation of the effector caspases. On the one hand, receptor systems may be involved on the other hand, activation may be triggered by cytotoxic stress. The two pathways differ in the mechanism of activation of the initiator caspase but use the same effector caspase at least partially. 

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). 

After activation of the ER stress sensors, IREl, PERK and ATF6, distinct signaling pathways are induced to regulate ER chaperones expression, degradation of protein through the ER associated protein degradation (ERAD) and expansion of the ER. If these events fail to restore ER homeostasis, Ca2-l- is released to activate apoptotic signaling pathways. 

Potential direct nephrotoxicity and the underlying molecular mechanisms were analyzed by in vitro studies in renal proximal tubular cells exposed to IFNa. IFNa was shown to induce apoptosis in LLC-PKl renal proximal tubular like epithelium [216]. Caspase-8, a key player in death receptor signaling and caspase-9 that is involved in mitochondrial apoptosis were shown to be activated in addition to caspase-3. Furthermore, IFNa induced a breakdown of the inner mitochondrial membrane potential, further implying mitochondrial signahng in IFNa-induced apoptosis. The deafh receptor pathway and the mitochondrial pathway appear to both be necessary for efficient executor caspase activation by IFNa. The apoptotic signaling pathways activated by IFNa in proximal tubular cells, thus, resemble the pathways induced by IFNa in melanoma and bladder carcinoma cells [217, 218]. In addition to caspase activation, nuclear condensation, DNA fragmentation and a delayed LDH release were observed. DNA fragmentation and LDH release were partially prevented by caspase inhibition. Thus, caspase-inde-pendent death is also possible - albeit delayed and at a reduced extent [216]. 

A procaspase is proteolytically activated by a caspase already activated upstream in the apoptotic signaling pathway. This mechanism is used particularly in the effector part of the apoptotic pathway. 

Recruitment of the initiator procaspases into a multiprotein complex results from a regulated series of protein-protein interactions mediated by interaction modules . Four types of interaction modules are involved in the activation of initiator caspases and thus play important roles in the initiation of apoptosis (review Weber and Vin-cenz, 2001). These domains have been named the death domain (DD),, the death effector domain (DED), the caspase activation and recruitment domain (CARD), and the less characterized pyrin domain. The domains are found on several components of the apoptotic signaling pathways and mediate homotypic protein-protein interactions, i. e., a given module will interact only with a member of the same family and not with members of the other families. Since members of the same module are found on different proteins, these modules mediate the assembly of hetero-oligomeric protein complexes. As examples, DDs are found on death receptors and their cofactors, D EDs on cofactors and the initiator caspase-8, and CARDS on cofactors, caspase-2, and caspase-9. 

The mitochondria have emerged as a central component of the intrinsic apoptotic signaling pathways and are now known to control apoptosis via the release of apopto-genic proteins (Fig.15.8). The apoptotic signals that are channeled through the mitochondrial pathway of apoptosis include various stresses like DNA damage, oxidative stress, UV radiation, protein kinase inhibition, and growth factor deprivation. 

Chatterjee et al. 2004), while others showed activation of apoptotic signaling pathways (Loidl et al. 2003). Recently, it was shown that POVPC caused phenotypic switching in SMC by suppressing the expression of multiple KLF4-dependent differentiation markers and induction of proinflammatory gene expression (Pidkovka et al. 2007). 

Budd SL, Tenneti L, Lishnak T, Lipton SA. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proc Natl Acad Sci USA. 2000 97 6161-6166... 

Resveratrol HepG2 cells Increase p21 expression and cause G1 phase arrest trigger p53-mediated molecules involved in the mechanism of p53-dependent apoptotic signal pathway [123]... 

Lopez-Anton, N., Rudy, A., Barth, N., Schmitz, L. M., Pettit, G. R., Schulze-Osthofif, K., Dirseh, V. M., Vollmar, A. M., 2006. The marine product cephalostatin 1 activates and ER stress -speeifie and apoptosome- independent apoptotic signaling pathway. J. Biol. Chem. 281,33078-33086. 

Several studies have investigated the effects of resveratrol and of several other stilbenoids on AD for their ability to modulate multiple mechanisms of AD pathology [60]. In vitro studies have shown that resveratrol may protect against the Ap peptide-induced toxicity in PC 12 neuronal cells or primary neurons by influencing apoptotic signaling pathways, reducing changes in mitochondrial... 

R. Vlvek, R. Thangam, V. Nipunbabu, T. Ponraj, and S. Kannan, Oxaliplatin-chitosan nanoparticles induced intrinsic apoptotic signaling pathway A smart drug delivery system to breast cancer cell therapy, Int. J. Biol. Macromol, 65,289-297, 2014. 

The predominant effect of flavonoid and isoflavonoid supplementation in ex vivo cell culture models appears to be one of promoting apoptosis [54—57]. This is repeatedly observed in studies witti transformed cancer cells, leading to the descriptions cytoprotective and/or chemopreventive [6,58]. Two poly-phenolic compounds that have been extensively studied in anticancer research are quercetin and genistein, a flavonoid and isoflavone, respectively. However, ex vivo studies with primary cultured cells in 2000 and 2001 showed that some flavonoids can prevent apoptosis promoted by agents that induce oxidative stress [7,8,59]. The outcome of flavonoid treatment is expected to show a complex dependence on a number of factors, including the type of flavonoid, its concentration, the type of cell (e.g., transformed versus nontransformed), the mechanisms of action of the flavonoid, the nature of the proapoptotic stimulus, and the specific apoptotic signaling pathway that is activated. 

There is a growing recognition that mitochondria play a central role in apoptosis [10,11], Mitochondria-dependent apoptotic pathways are responsive to intrinsic proapoptotic stimuli that cause perturbations in the intracellular environment, particularly oxidative stress. In addition, other apoptotic signaling pathways appear to converge onto the mitochondria. This raises the question of whether flavonoids may modulate events upstream or downstream of the mitochondria-dependent apoptotic cascade, in addition to their potential effect on mitochondrial respiration, oxidative phosphorylation, and oxyradical generation (as discussed earlier). 

Other Apoptotic Signaling Pathways Involved in Cadmium Toxicity... 

Ceramides have long been known to be intimately involved in apoptotic signaling pathways [540]. Ceramides induce cytochrome c release via ceramide channel formation [541] or activate Ca -dependent proteases, calpains [542]. Our laboratory were the first to show that Cd " increases ceramide formation, possibly via de novo synthesis, which activates calpain activity by increasing cytosolic Ca ". Apoptosis was then executed in a caspase-independent manner [542]. Interestingly, ceramide and its metabolites are also implicated in multidrug resistance and evasion of apoptosis in tumor cells (see Section 5.8). Active calpains cleave a wide array of substrates that can lead to apoptosis as well as survival and autophagy [543]. Apoptotic substrates include caspases, Bcl-2, Bax, and AIF. In Cd -treated cells, calpains are activated at early time points (3-6 hours) and provide a point for crosstalk with caspases, which are activated later (24 hours) [522] and can also cleave Bax to release cytochrome c [528]. 

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