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Phospholipase D in cellular senescence.

M E Venable1, L M Obeid

  • 1Biology Department, Appalachian State University, P.O. Box 32027, Boone, NC 28608-2027, USA. venableme@appstate.edu

Biochimica Et Biophysica Acta
|July 30, 1999
PubMed
Summary

Cellular senescence, a hallmark of aging, involves defective early mitotic signals like the Phospholipase D (PLD)/Protein Kinase C (PKC) pathway. Elevated ceramide levels inhibit PLD activation, driving senescence.

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Area of Science:

  • Cellular and Molecular Biology
  • Gerontology
  • Biochemistry

Background:

  • Cellular senescence is a key process in organismal aging, characterized by distinct morphological and molecular changes.
  • Key features include growth arrest, altered gene expression (e.g., p21, p16), and defective early mitotic signaling pathways.
  • The Phospholipase D (PLD)/Protein Kinase C (PKC) pathway is crucial for cell proliferation (mitogenesis).

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the defect in the PLD/PKC pathway during cellular senescence.
  • To identify the role of ceramide in the pathogenesis of cellular senescence.

Main Methods:

  • Analysis of gene and protein expression in senescent cells.
  • Investigation of PLD and PKC pathway activation.
  • Experimental manipulation of ceramide levels in young and senescent cells.

Main Results:

  • Cellular senescence is associated with a defective PLD/PKC signaling pathway.
  • Elevated cellular ceramide levels were identified as a cause of PLD activation inhibition.
  • Neutral sphingomyelinase activation appears to be responsible for increased ceramide.
  • Ceramide inhibits PLD activation through multiple mechanisms, including interference with Rho signaling, membrane translocation, and gene expression.
  • Exogenous ceramide addition to young cells induced typical senescence phenotypes.

Conclusions:

  • Elevated ceramide, resulting from neutral sphingomyelinase activation, is a critical mediator of cellular senescence by inhibiting the PLD/PKC pathway.
  • Targeting ceramide metabolism or PLD/PKC signaling may offer therapeutic strategies for age-related conditions.

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