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Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
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Mitogen- and stress-activated protein kinases 1 and 2 are required for maximal trefoil factor 1 induction

Protiti Khan1, Bojan Drobic, Beatriz Pérez-Cadahía

  • 1Manitoba Institute of Child Health, University of Manitoba, Winnipeg, Manitoba, Canada.

Plos One
|May 16, 2013
PubMed

Insights

Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) regulate breast cancer gene TFF1 expression by phosphorylating histone H3. This promotes chromatin remodeling and gene activation, with MSK1 and MSK2 acting in distinct complexes.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Epigenetics

Background:

  • Mitogen- and stress-activated protein kinases 1 and 2 (MSK1 and MSK2) are key regulators of cellular responses to mitogenic and stress stimuli.
  • These kinases mediate the nucleosomal response, including histone H3 serine 10 phosphorylation (H3S10ph), crucial for immediate-early gene activation.
  • Research has primarily focused on MSK1, with limited understanding of MSK2's role in gene regulation.

Purpose of the Study:

  • To investigate the roles of both MSK1 and MSK2 in regulating the expression of the breast cancer marker gene, trefoil factor 1 (TFF1).
  • To elucidate the molecular mechanisms by which MSK1 and MSK2 control TFF1 gene transcription.
  • To determine the specific recruitment patterns of MSK1 and MSK2 to TFF1 regulatory regions.

Main Methods:

  • Utilized phorbol ester (12-O-tetradecanoylphorbol-13-acetate) to induce TFF1 expression in MCF-7 breast cancer cells.
  • Investigated histone H3 serine 10 phosphorylation (H3S10ph) at TFF1 regulatory regions.
  • Assessed the recruitment of MSK1, MSK2, 14-3-3 isoforms, BRG1, and RNA polymerase II to the TFF1 promoter and enhancer elements.

Main Results:

  • Both MSK1 and MSK2 were found to regulate TFF1 expression by phosphorylating H3S10 in its 5' regulatory regions.
  • MSK-mediated H3S10ph facilitated the recruitment of 14-3-3 isoforms and BRG1 to TFF1 enhancer and promoter regions.
  • Recruitment of chromatin remodeling complexes led to RNA polymerase II C-terminal domain phosphorylation and initiation of TFF1 expression.
  • MSK1 and MSK2 were recruited to TFF1 regulatory regions as components of distinct multiprotein complexes.

Conclusions:

  • MSK1 and MSK2 play significant, albeit distinct, roles in regulating TFF1 gene expression in breast cancer cells.
  • The MSK-mediated signaling pathway involving H3S10ph, chromatin remodeling, and RNA polymerase II activation is critical for TFF1 induction.
  • Understanding the differential recruitment of MSK1 and MSK2 offers insights into context-dependent gene regulation.

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