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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

TGFbeta activates mitogen- and stress-activated protein kinase-1 (MSK1) to attenuate cell death

Lars P van der Heide1, Maarten van Dinther, Aristidis Moustakas

  • 1Department of Molecular Cell Biology, and Centre for Biomedical Genetics, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, The Netherlands. lars.vdh@LICR.uu.se

The Journal of Biological Chemistry
|November 26, 2010
PubMed

Insights

Mitogen- and stress-activated kinase 1 (MSK1) acts as a survival pathway, opposing transforming growth factor-beta (TGFβ)-induced cell death. MSK1 inactivation enhances TGFβ-induced apoptosis, suggesting therapeutic potential in cancer.

Area of Science:

  • Cellular signaling pathways
  • Molecular mechanisms of apoptosis
  • Cancer biology

Background:

  • Transforming growth factor-beta (TGFβ) signaling is crucial for cellular processes, including apoptosis.
  • Smad proteins mediate TGFβ-induced gene transcription.
  • The role of mitogen- and stress-activated kinase 1 (MSK1) in TGFβ signaling and cell death remains incompletely understood.

Purpose of the Study:

  • To investigate the role of MSK1 as a regulator of TGFβ-induced cell death.
  • To elucidate the molecular mechanisms by which MSK1 influences apoptosis.
  • To explore the potential of targeting MSK1 and EGF signaling in cancer therapy.

Main Methods:

  • Investigated MSK1 activity in response to TGFβ stimulation.
  • Utilized knockdown of GADD45 and MSK1 to assess their impact on signaling pathways.
  • Analyzed the phosphorylation status of pro-apoptotic BH3-only BCL2 proteins (Bad, Noxa, Bim).
  • Measured caspase-3 activity to quantify apoptosis.
  • Examined the effects of Epidermal Growth Factor (EGF) on MSK1 knockdown phenotypes.

Main Results:

  • TGFβ induces MSK1 activity, dependent on Smad4 and p38 MAPK.
  • GADD45 knockdown abrogates TGFβ-induced p38 and MSK1 activation.
  • MSK1 knockdown enhances TGFβ-induced apoptosis by reducing Bad phosphorylation and increasing Noxa and Bim expression.
  • MSK1 acts as a pro-survival pathway downstream of p38 MAPK.
  • EGF signaling can reverse the effects of MSK1 knockdown.

Conclusions:

  • MSK1 functions as a pro-survival factor that antagonizes TGFβ-induced apoptosis.
  • The p38 MAPK pathway bifurcates, with MSK1 promoting survival and other effectors driving apoptosis.
  • Targeting MSK1 and EGF signaling may re-sensitize cancer cells to TGFβ-induced death.

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