Cited by 59Sphingolipid Metabolism and SignalingCancer-related Molecular PathwaysCancer, Lipids, and Metabolism

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

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Fekry, Baharan, Jeffries, Kristen A., Esmaeilniakooshkghazi, Amin, Ogretmen, Besim, Krupenko, Sergey A., Krupenko, Natalia I.·2016·Journal of Biological Chemistry

Abstract

Our previous study suggested that ceramide synthase 6 (CerS6), an enzyme in sphingolipid biosynthesis, is regulated by p53: CerS6 was elevated in several cell lines in response to transient expression of p53 or in response to folate stress, which is known to activate p53. It was not clear, however, whether CerS6 gene is a direct transcriptional target of p53 or whether this was an indirect effect through additional regulatory factors. In the present study, we have shown that the CerS6 promoter is activated by p53 in luciferase assays, whereas transcriptionally inactive R175H p53 mutant failed to induce the luciferase expression from this promoter. In vitro immunoprecipitation assays and gel shift analyses have further demonstrated that purified p53 binds within the CerS6 promoter sequence spanning 91 bp upstream and 60 bp downstream of the transcription start site. The Promo 3.0.2 online tool for the prediction of transcription factor binding sites indicated the presence of numerous putative non-canonical p53 binding motifs in the CerS6 promoter. Luciferase assays and gel shift analysis have identified a single motif upstream of the transcription start as a key p53 response element. Treatment of cells with Nutlin-3 or low concentrations of actinomycin D resulted in a strong elevation of CerS6 mRNA and protein, thus demonstrating that CerS6 is a component of the non-genotoxic p53-dependent cellular stress response. This study has shown that by direct transcriptional activation of CerS6, p53 can regulate specific ceramide biosynthesis, which contributes to the pro-apoptotic cellular response.

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  • Apoptosis can be activated by ceramide, and p53 appears to directly upregulate the ceramide synthase-encoding genes CERS5 and CERS6 and to induce ceramide production.

    “Apoptosis also can be activated by ceramide,186 and p53 appears to directly upregulate the ceramide synthase-encoding genes CERS5 (Table 1) and CERS6187 and to induce ceramide production.188”

    From Census and evaluation of p53 target genes (2017) · cites this paper as [187]

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Authors
Fekry, B., Jeffries, K. A., Esmaeilniakooshkghazi, A., Ogretmen, B., Krupenko, S. A., & Krupenko, N. I.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Krupenko, Natalia I.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2016-08
Volume
291
Issue
32
Pages
16586-16596
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2442260070
Cited by
59
References
61
Citations by year
2026: 4 · 2025: 6 · 2024: 5 · 2023: 10 · 2022: 1 · 2021: 10 · 2020: 4 · 2019: 6 · 2018: 6 · 2017: 5 · 2016: 2
FWCI
3.29
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
National Institutes of Health (CA193782, CA88932, CA97165, DK54388, DE16572)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
ceramide synthase 6, p53, transcriptional activation, ceramide biosynthesis, sphingolipid metabolism, p53 response elements, promoter binding, Nutlin-3, actinomycin D, apoptosis
MeSH terms
A549 Cells, Ceramides, Humans, Imidazoles, Membrane Proteins, Piperazines, Stress, Physiological, Transcription, Genetic, Tumor Suppressor Protein p53, Amino Acid Substitution, Mutation, Missense, Response Elements, Sphingosine N-Acyltransferase, Nucleotide Motifs

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