Yusuf Awni Hannun

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..Because sphingolipid metabolism has been reported to be altered in drug-resistant tumor cells, we studied the implication of sphingolipids in acquired resistance to 4-HPR based on an acute lymphoblastic leukemia model...

..They do this by regulating enzymes involved in its metabolism. Ceramide modulates a number of biochemical and cellular responses to stress, including apoptosis, cell-cycle arrest and cell senescence...

..Taken together, the results provide, for the first time, a mechanism that assures the coordinate expression and activation in time and space of COX-2 and cPLA(2), assuring maximal production of PGE(2)...

..The studies also begin to define features that transform ceramide analogs into inhibitors of CAPP...

..Deciphering the mechanisms of these varied cell functions necessitates an understanding of the complex pathways of sphingolipid metabolism and the mechanisms that regulate lipid generation and lipid action...

..This may be a general prototype for the involvement of metabolic pathways in cell regulation...

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..In this minireview, we describe the "many ceramides" paradigm, along with the rationale, supporting evidence, and implications for our understanding of bioactive sphingolipids and approaches for unraveling these pathways...

..In conclusion, these results 1) show that nSMase2 is a structural gene for nSMase, 2) suggest that nSMase2 acts as a bona fide N-SMase in cells, and 3) implicate nSMase2 in the regulation of cell growth and cell signaling...

..Effects of treatment on cytotoxicity, sphingolipid content, and apoptotic markers were assessed...

..In conclusion, these data suggest an important role for LASS1/C(18)-ceramide in gemcitabine/doxorubicin-induced cell death via the activation of caspase-9/3 in HNSCC...

..However, some active analogs of the d-e-MAPP family were selective against different types of cancer. Compounds LCL85, LCL120, LCL385, LCL284, and LCL204 were identified to be promising lead compounds for therapeutic development...

..Therefore, these studies show that SK1 down-regulation by TNF is dependent on the "lysosomal pathway" of apoptosis and specifically on cathepsin B, which functions as an SK1 protease in cells...

..These studies for the first time implicate endogenous SK1 as an important survival enzyme in MCF-7 cells and link the biological consequences of knocking down the enzyme to its biochemical role as a regulator of sphingolipid metabolism...

..An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer...

..These studies demonstrate that SK1 is down-regulated by genotoxic stress, and that basal SK1 function may be necessary for the maintenance of tumor cell growth...

..This study identifies previously unknown roles for ceramide kinase and its product, C-1-P, in AA release and production of eicosanoids and provides clues for potential new targets to block inflammatory responses...

..These findings may provide insights into the many systems in which de novo synthesis is increased in the absence of elevated in vitro SPT activity...

..Inhibition of SK1 may prove to be a valuable therapeutic target by inhibiting systemic and local inflammation in IBD...

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..This is the first report on the dynamic regulation of RNA splicing of members of the Bcl-2 and caspase families in response to regulators of apoptosis...

..In conclusion, this study demonstrates, for the first time, a biological role for LAG1 and C18-ceramide in the regulation of growth of HNSCC...

..Furthermore, the p38delta isoform was identified as a novel and predominant target of ceramide signaling as well as a regulator of IL-6 biosynthesis...

..The approach also defines a tool kit to probe sphingolipid signaling at the plasma membrane...

..These data reveal p38 MAPK as an upstream regulator of nSMase2 and indicate a role for nSMase2 in pro-inflammatory responses induced by TNF-alpha as a regulator of adhesion proteins...

..Taken together, these results establish a novel direct biochemical mechanism for ASMase activation in which PKCdelta serves as a key upstream kinase...

..01) in apoptosis over either treatment modality alone. Together, these data suggest that apoptin modulates ceramide/sphingolipid metabolism as part of its mechanism of action...

..Taken together, this study provides key molecular insights into activation of ASMase in response to UV light, the role of PKCdelta in this activation, and the role of ASMase in mediating apoptotic responses...

..Finally, evidence is provided for a role for this pathway in regulating cell motility during confluence...

..Collectively, GBA1 is identified as a novel source of regulated formation of ceramide, and PKCdelta is an upstream regulator of this pathway...

..alpha-Hydroxylated Cer demonstrated considerably higher affinity, indicating a preference of the enzyme to those Cer molecular species. These results disclose a very high specificity of nonlysosomal CDase for its substrate, Cer...

..Based on these findings, this study indicates that SK1 and S1P could be implicated in pathological inflammatory disorders and cancer...

..Together, these results suggest that sphingosine generated from hydrolysis of ceramide causes the GC disruption, leading to various cellular effects...

..Together, these experiments demonstrate that SphK/S1P are important components of the TGF-beta signaling pathway involved in up-regulation of the TIMP-1 gene...

..This is the first report of selective function of dhS1P as compared with the better studied S1P...

..Hence, we demonstrate for the first time that nSMase2 functions as a growth suppressor in MCF7 cells, linking confluence to the G(0)/G(1) cell cycle check point...

..CONCLUSIONS: These data suggest that the novel C6-Pyr-Cer with high solubility and bioavailability may lead to the development of new therapeutic strategies that target telomerase for the treatment of HNSCC...

..Taken together, these data implicate PKC-delta as a regulator of nSMase2 and, for the first time, identify nSMase2 as a point of cross-talk between the PKC and sphingolipid pathways...

..NCDase siRNA also induced Rb dephosphorylation. These data provide evidence for a novel mechanism of action for GMZ and highlight downregulation of NCDase as a critical step in GMZ-mediated ceramide elevation and cell cycle arrest...

..Moreover, SR dephosphorylation is emerging as a specific downstream target of accumulation of newly made ceramides in mammalian cells...

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..Taken together, these results define a novel role for AC in the TNFalpha/PGE(2) pathway. In addition, the results of this study warrant careful reconsideration of desipramine as a specific inhibitor for ASMase...

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..These data demonstrate that the sphingosine-recycling pathway for the generation of endogenous long-chain ceramide in response to exogenous C6-cer is regulated by ROS, and plays an important biological role in controlling c-Myc function...

..This review is geared at mechanisms of regulation of sphingosine kinase and the coming to light of its role in disease...

..How a single gene product has the capacity to function in these diverse settings, and the subsequent impact on downstream ceramide-mediated biology is the subject of this review...

..Thus, these data reveal an unexpected and novel prosurvival role of CerS6/C(16)-ceramide involved in the protection against ER-stress-induced apoptosis and induction of HNSCC tumor growth...

..Per particle, VLDL contained the highest levels of SM, Cer, and S1P. HPLC-MS/MS should provide a tool for clinical testing of circulating bioactive sphingolipids in human blood...

..These results suggest that the SK1/S1P pathway may play an important role in colon carcinogenesis, in part, by regulating COX-2 expression and PGE2 production...

..This and related methodology are already defining unexpected specialization and specificity in the metabolism and function of distinct subspecies of individual bioactive SPLs...

..aeruginosa infection. This study demonstrates that the defective ASMase pathway in CF is a key contributor to the unabated IL-8 response with P. aeruginosa infection and to the compromised host response failing to eradicate bacteria...

..Taken together, these findings implicate Isc1p as an upstream regulator of Swe1p levels and stability and Cdc28-Tyr-19 phosphorylation, in effect signaling recovery from the effects of genotoxic stress and allowing G(2)/M progression...

..When these results were taken together with the known crystallographic structure of PP1, they identified a novel PA binding region on PP1c gamma that contains a unique loop-strand structural fold responsible for the interaction with PA...

..This SM synthase did not have reverse transferase activity. In conclusion, the Pseudomonas PlcH also exerts SM synthase activity; therefore, for the first time, we have identified a structural gene for a SM synthase...

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..Our results suggest that ceramide plays a role in promoting TRAIL-mediated apoptosis and that TRAIL-resistant cancers may benefit from combination therapy with ceramide or agents that enhance ceramide accumulation...

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..These novel analogs should be useful in cell-based studies as specific regulators of Cer-Sph-S1P inter-metabolism, in vitro enzymatic studies, and for therapeutic development...

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..Defining hyaluronan-dependent cyclooxygenase-2/prostaglandin E(2)-associated signaling pathways will provide a platform for developing novel therapeutic approaches for colon cancer...

..Tautomycin was also able to block the hypophosphorylation of the retinoblastoma protein observed upon fenretinide treatment. These findings suggest a novel biological function for dihydroceramides...

..In this Perspective, we examine the evidence for these connections in yeast, Drosophila, and mammals, and speculate on their implications...

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..These studies should generate significant insight into novel aspects of signal transduction, regulation of phosphatases, and the regulation of cancer cell growth. ..

..These pathways are of direct significance to the biology of stress responses and specifically to cancer biology and inflammation. ..

..The proposal endeavors to use biochemical, molecular as well as mathematical approaches that allow a deeper understanding of the stress response at a semi-comprehensive level, commensurate with the post-genomic era of research. ..

..This model system could then serve as a conceptual and practical platform to extend the hypothesis to other lipid classes, other aspects of regulated metabolism, and eventually to mammalian metabolism. ..

..These pathways are of direct significance to the biology of stress responses and specifically to cancer therapeutics. ..

..We are defining the significance and mechanisms by which this process occurs and is regulated. In particular we focus on a key signaling protein known as protein kinase C (PKC) and its activating lipids. ..

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..These studies should generate significant insight into novel aspects of signal transduction, regulation of phosphatases, and the regulation of cancer cell growth. ..

..The studies should also result in the identification of novel strategies for cancer therapeutics aimed at inducing cancer cell death and/or inhibition of tumor angiogenesis. ..

..These may have important implications in the study of cancer biology and therapeutics. ..

..4. Foster and further develop ongoing interdisciplinary research Among the various users. ..

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..N-SMase may emerge as a key target in the understanding of the mechanisms of the stress response and in therapeutic development. ..

..These studies are beginning to define novel signaling pathways that regulate distinct sub-families of PKC, with important implications for the understanding of tumor promotion, apoptosis and the other critical events regulated by PKC. ..

..These pathways are of direct significance to the biology of stress responses and specifically to cancer therapeutics. ..