Programmed cell death is an important physiological response to many forms of cellular stress. such as irradiation . The effects of ceramide are pleiotropic but for the most part growth inhibiting. The molecule has been implicated in differentiation [26 27 cell cycle arrest [28-30] apoptosis  and senescence  in several cell types. It induces cell cycle arrest through the dephosphorylation of the Retinoblastoma gene product (Rb) activation of the cyclin dependent kinase inhibitor p21 and inhibition of the cyclin dependent kinase 2 (CDK2) [29 30 33 These studies have shown that ceramide is definitely upstream of cell cycle regulators and AZD7762 that the generation of ceramide is necessary for growth arrest in response to stimuli that induce this arrest. The elevation of ceramide has also been shown to occur in senescent cells probably via the activation of neutral sphingomyelinase (nSMase) . The senescent phenotype may be attributed to a defect in the phospholipase D/ protein kinase C (PLD/PKC) pathway and ceramide can inhibit both PLD and PKC [35-37]. AZD7762 Number 2 Ceramide is definitely a central mediator of many apoptotic pathways Probably one of the most analyzed tasks of ceramide pertains to its function as a proapoptotic molecule. The build up of ceramide following treatment of cells with apoptotic providers offers implicated this lipid in the biological responses of these agents . Because of its apoptosis-inducing effects in malignancy cells ceramide has been termed the “tumor suppressor lipid” . Several studies have attempted to define further the specific part of ceramide in the events of cell death. The tumor suppressor protein p53 the Bcl-2 family of proteins and several protease classes are all key components of the tumor response to stress insults and ceramide has been linked to each of these mediators. Many studies however report variable associations among these proteins and ceramide suggesting that different cells have dissimilar networks and that deciphering the relevance of findings to tumor behavior is definitely far from recognized. 2.1 Ceramide and p53 Several studies possess generated conflicting data on the relationship between ceramide and p53 which is virtually dysfunctional in all human tumors. While some reports display that p53 is definitely upstream of ceramide in tumor stress reactions [39 40 additional studies implicate p53 like a downstream target [41-43] yet these latter studies use exogenous ceramide as the stress inducer whereas the former use providers that generate endogenous ceramide. Still additional observations place ceramide and p53 in two independent and self-employed pathways in the apoptotic process [44 45 In the second option case treatment with chemotherapeutic providers generates ceramide in p53+/+ as well as p53-/- cells. One study has shown that ceramide can be created by acid sphingomyelinase (aSMase) in response to genotoxic stress only in cells lacking functional p53 suggesting that p53 can inhibit aSMase activation and ceramide generation . Studies by Santana et al. also proposed Rabbit Polyclonal to MARK3. a role for aSMase derived ceramide in the apoptotic response and highlighted the response is different from that derived by p53 driven cellular responses . Therefore it remains unclear how ceramide and p53 are linked in PCD and there appears to be variations in the link between the two messengers in different cell death models. 2.2 Ceramide and the Bcl-2 Family An equally wide array of studies has investigated the relationship between ceramide and the Bcl-2 family of proteins both following treatment with genotoxic and nongenotoxic providers. The most analyzed contacts AZD7762 pertain to Bcl-2 itself Bcl-xL and Bax. The position of ceramide with respect to Bcl-2 is definitely variably reported. A number of groups have shown that ceramide is definitely upstream of Bcl-2 in the apoptotic pathway since Bcl-2 overexpression rescues from cell death induced by ceramide  or by ceramidase inhibitors . Moreover El-Assaad et al. have shown that Bcl-2 and Bcl-xL define two different points of rules of ceramide reactions. While both proteins save from TNF mediated cell death only Bcl-xL abrogates ceramide generation while Bcl-2 does not implying a pathway where ceramide is definitely downstream of Bcl-xL but upstream AZD7762 of Bcl-2 . Moreover in C6 glioma cells etoposide induces ceramide formation by neutral sphingomyelinase activation which then increases the Bax/Bcl-2 percentage  and in A549 cells exogenous.