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Updated: Aug 13, 2026

Techniques to Induce and Quantify Cellular Senescence
06:51

Techniques to Induce and Quantify Cellular Senescence

Published on: May 1, 2017

Protein kinase C delta blocks immediate-early gene expression in senescent cells by inactivating serum response

Keith Wheaton1, Karl Riabowol

  • 1Department of Biochemistry and Molecular Biology, Southern Alberta Cancer Centre, University of Calgary, Calgary, Alberta, Canada.

Molecular and Cellular Biology
|July 30, 2004
PubMed

Insights

Cellular senescence involves the loss of growth factor response and gene expression. Protein kinase C delta (PKC delta) inactivates the serum response factor (SRF), contributing to this senescent phenotype.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Cellular senescence is characterized by impaired growth factor response and reduced expression of immediate-early genes like c-fos and egr-1.
  • The serum response factor (SRF) is crucial for activating immediate-early gene promoters but loses DNA binding ability in senescent cells.
  • SRF inactivation in senescent cells is linked to hyperphosphorylation and reduced binding to the serum response element (SRE).

Purpose of the Study:

  • To identify the specific kinase responsible for SRF inactivation in senescent fibroblasts.
  • To elucidate the mechanism by which this kinase leads to SRF dysfunction.
  • To investigate the potential of targeting this kinase to reverse senescence-associated gene expression changes.

Main Methods:

  • In vitro and endogenous assays to determine the kinase activity responsible for SRF phosphorylation.
  • Analysis of protein kinase C delta (PKC delta) activity, catalytic fragment production, and nuclear localization in senescent versus young cells.
  • Inhibition of PKC delta using rottlerin and dominant-negative PKC delta expression to assess effects on SRE-dependent transcription and gene expression.
  • In vivo modulation of PKC delta activity to observe effects on cell morphology.

Main Results:

  • Protein kinase C delta (PKC delta) was identified as the kinase that inactivates SRF in senescent cells.
  • Increased PKC delta activity, catalytic fragment production, and nuclear localization were observed in senescent cells.
  • PKC delta phosphorylates SRF at T160, leading to loss of DNA binding activity.
  • PKC delta inhibition or dominant-negative expression restored SRE-dependent transcription and immediate-early gene expression in senescent cells.
  • Modulation of PKC delta activity affected senescent and young cell morphology.

Conclusions:

  • PKC delta plays a critical role in the transcriptional repression of growth-associated genes during cellular senescence.
  • The increased activity and nuclear localization of PKC delta contribute to the senescent phenotype by inactivating SRF.
  • Targeting PKC delta activity presents a potential therapeutic strategy for modulating cellular senescence.

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