2. Academic Validation
  3. C16-ceramide is a natural regulatory ligand of p53 in cellular stress response

C16-ceramide is a natural regulatory ligand of p53 in cellular stress response

  • Nat Commun. 2018 Oct 8;9(1):4149. doi: 10.1038/s41467-018-06650-y.
Baharan Fekry 1,  Kristen A Jeffries 1,  Amin Esmaeilniakooshkghazi 1,  Zdzislaw M Szulc 2 3,  Kevin J Knagge 4,  David R Kirchner 4,  David A Horita 1,  Sergey A Krupenko 1 5,  Natalia I Krupenko 6 7
Affiliations

Affiliations

  • 1 University of North Carolina at Chapel Hill Nutrition Research Institute, Kannapolis, NC 28081, USA.
  • 2 Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
  • 3 Lipidomics Facility, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC, 29425, USA.
  • 4 David Murdock Research Institute, Kannapolis, NC 28081, USA.
  • 5 Department of Nutrition, UNC Chapel Hill, Chapel Hill, NC 27599, USA.
  • 6 University of North Carolina at Chapel Hill Nutrition Research Institute, Kannapolis, NC 28081, USA. natalia_krupenko@unc.edu.
  • 7 Department of Nutrition, UNC Chapel Hill, Chapel Hill, NC 27599, USA. natalia_krupenko@unc.edu.
PMID: 30297838 DOI: 10.1038/s41467-018-06650-y
Abstract

Ceramides are important participants of signal transduction, regulating fundamental cellular processes. Here we report the mechanism for activation of p53 tumor suppressor by C16-ceramide. C16-ceramide tightly binds within the p53 DNA-binding domain (Kd ~ 60 nM), in close vicinity to the Box V motif. This interaction is highly selective toward the ceramide acyl chain length with its C10 atom being proximal to Ser240 and Ser241. Ceramide binding stabilizes p53 and disrupts its complex with E3 Ligase MDM2 leading to the p53 accumulation, nuclear translocation and activation of the downstream targets. This mechanism of p53 activation is fundamentally different from the canonical p53 regulation through protein-protein interactions or posttranslational modifications. The discovered mechanism is triggered by serum or folate deprivation implicating it in the cellular response to nutrient/metabolic stress. Our study establishes C16-ceramide as a natural small molecule activating p53 through the direct binding.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z