CerS6 Is a Novel Transcriptional Target of p53 Protein Activated by Non-genotoxic Stress

Fekry, Baharan; Jeffries, Kristen A.; Esmaeilniakooshkghazi, Amin; Öğretmen, Besim; Krupenko, Sergey A.; Krupenko, Natalia I.

doi:10.1074/jbc.m116.716902

Cited by 48 publications

(28 citation statements)

References 57 publications

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“…Mechanistically, melanoma cells exhibited increased platelet secretory ASMase activity, which induced C16 ceramide formation and led to activation and clustering of α5β1 integrin on melanoma cells, thereby promoting cancer cell adhesion and metastasis 47 . These data suggest that although induction of ASMase in cancer cells results in apoptosis, systemic ASMase activation in platelets leads to increased melanoma metastasis, highlighting the importance of cell-type-specific expression of enzymes involved in ceramide signalling in inducing cell death versus increasing survival and/or migration, similar to CERS6–C16 ceramide signalling in lung cancer (apoptotic) 35 versus HNSCC (survival) 41 cells.…”

Section: Sphingolipid Metabolism and Cancermentioning

confidence: 88%

“…Approximately 50% of mice with germline loss of Cers2 , which is involved in reduction of long-chain (C22–24) ceramides, developed pheochromocytoma owing to possible defects in apoptosis 34 . Moreover, CERS6-generated C16 ceramide was identified as a transcriptional target of p53 that is activated by non-genotoxic folate stress to induce cell death in p53 wild-type human lung cancer cells 35 . CERS6-generated C16 ceramide was also shown to increase tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitivity by inducing nuclear translocation of caspase 3 in colon cancer cells 36 .…”

Section: Sphingolipid Metabolism and Cancermentioning

confidence: 99%

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Sphingolipid metabolism in cancer signalling and therapy

2017

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Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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Section: Sphingolipid Metabolism and Cancermentioning

confidence: 88%

Section: Sphingolipid Metabolism and Cancermentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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“…EMSA provides a tool for investigation of protein and DNA interaction (Fekry et al., ; Wang et al., ). In most EMSA assays, nuclear extract was directly incubated with DNA probes that were designed and synthesized to cover putative TFBSs (Fekry et al., ; Wang et al., ). Transcription factor in the nuclear extract can bind to the DNA probe that contains the real targeted TFBS.…”

Section: Discussionmentioning

confidence: 99%

Identifying the location of epidermal growth factor‐responsive element involved in the regulation of type IIb sodium‐phosphate cotransporter expression in porcine intestinal epithelial cells

Xing

Tan

et al. 2016

Animal Physiology Nutrition

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Phosphate is an important mineral nutrient for both human and animals in growth and physiological functions; thus, much effort in the past has been made to clarify the mechanisms governing its absorption. Previous studies have found that epidermal growth factor (EGF) inhibits phosphate absorption in human intestinal cells via modulating the interaction of transcriptional factor c-myb with sodium-phosphate cotransporter (NaPi-IIb) gene promoter. This finding provoked our interest in determining the effect of EGF on NaPi-IIb gene expression in intestinal cells of pigs and the location of EGF-responsive element in the gene promoter. Using quantitative PCR, it was observed that EGF significantly reduced NaPi-IIb gene expression in porcine intestinal epithelial IPEC-J2 cells. Transfection with a series of constructs that contain different lengths of the 5'-flanking promoter region of the NaPi-IIb gene manifested that EGF-responsive element is located in the -1200 to -800 region. Further, c-myb was extracted from the cell nucleus of IPEC cells that were exposed to EGF or not via immunoprecipitation. The electrophoretic mobility shift assay showed a specific binding of transcription factor c-myb to labelled probes encompassing DNA sequence from -1092 to -1085 (-TCCAGTTG-). This protein-DNA complex was decreased with cells exposed to EGF and abrogated when c-myb was pre-incubated with excessive unlabelled competitive probes. Results from mutagenesis studies demonstrated that the c-myb-binding site is the EGF-responsive element involved in the regulation of NaPi-IIb expression. Identifying the location of EGF-responsive element contributes to understanding mechanisms underlying EGF down-regulated NaPi-IIb gene expression and provides a foundation for further investigating EGF-regulatory functions in phosphate absorption in pig intestine.

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“…Another ceramide synthase, CerS6, was recently found to be directly transcriptionally activated by p53 via a noncanonical binding site, 11 nucleotides upstream of transcription start site (Fekry, Jeffries, et al, 2016). In contrast to the upregulation of ceramide synthases, SPHK1, a sphingolipid enzyme balancing the ceramide/S1P rheostat (Baran et al, 2007), was shown to be downregulated by p53 (Heffernan-Stroud et al, 2012; Taha et al, 2004).…”

Section: P53 and Ceramide Pathwaysmentioning

confidence: 99%

Ceramide Signaling and p53 Pathways

Jeffries¹,

Krupenko

2018

Advances in Cancer Research

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Ceramides, important players in signal transduction, interact with multiple cellular pathways, including p53 pathways. However, the relationship between ceramide and p53 is very complex, and mechanisms underlying their coregulation are diverse and not fully characterized. The role of p53, an important cellular regulator and a transcription factor, is linked to its tumor suppressor function. Ceramides are involved in the regulation of fundamental processes in cancer cells including cell death, proliferation, autophagy, and drug resistance. This regulation, however, can be pro-death or pro-survival depending on cancer type, the balance between ceramide species, the rate of their synthesis and utilization, and the availability of a specific array of downstream targets. This chapter highlights the central role of ceramide in sphingolipid metabolism, its role in cancer, specific effectors in ceramide pathways controlled by p53, and coregulation of ceramide and p53 signaling. We discuss the recent studies, which underscore the function of p53 in the regulation of ceramide pathways and the reciprocal regulation of p53 by ceramide. This complex relationship is based on several molecular mechanisms including the p53-dependent transcriptional regulation of enzymes in sphingolipid pathways, the activation of mutant p53 through ceramide-mediated alternative splicing, as well as modulation of the p53 function through direct and indirect effects on p53 coregulators and downstream targets. Further insight into the connections between ceramide and p53 will allow simultaneous targeting of the two pathways with a potential to yield more efficient anticancer therapeutics.

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CerS6 Is a Novel Transcriptional Target of p53 Protein Activated by Non-genotoxic Stress

Cited by 48 publications

References 57 publications

Sphingolipid metabolism in cancer signalling and therapy

Sphingolipid metabolism in cancer signalling and therapy

Identifying the location of epidermal growth factor‐responsive element involved in the regulation of type IIb sodium‐phosphate cotransporter expression in porcine intestinal epithelial cells

Ceramide Signaling and p53 Pathways

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