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Phosphorylation of Ser28 in histone H3 mediated by mixed lineage kinase-like mitogen-activated protein triple kinase

Hong Seok Choi1, Bu Young Choi, Yong-Yeon Cho

  • 1Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.

The Journal of Biological Chemistry
|February 3, 2005
PubMed

Insights

Mixed lineage kinase-like triple kinase-alpha (MLTK-alpha) phosphorylates histone H3 at Ser28, a key step in gene activation. This study identifies MLTK-alpha as a novel histone H3 kinase involved in cellular responses to UVB and EGF.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Epigenetics

Background:

  • Mitogen-activated protein kinase (MAPK) cascades regulate gene expression through chromatin modification.
  • Histone H3 phosphorylation is a critical event in gene activation.
  • The specific kinases involved in histone H3 phosphorylation at Ser28 are not fully elucidated.

Purpose of the Study:

  • To identify the specific kinase responsible for histone H3 phosphorylation at Ser28.
  • To investigate the role of mixed lineage kinase-like triple kinase-alpha (MLTK-alpha) in this process.
  • To determine the involvement of MLTK-alpha in cellular responses to ultraviolet B (UVB) and epidermal growth factor (EGF).

Main Methods:

  • In vitro and in vivo kinase assays using MLTK-alpha and histone H3.
  • Overexpression of MLTK-alpha in 293T and JB6 Cl41 cells.
  • Treatment with UVB and EGF to stimulate cells.
  • Inhibition studies using kinase inhibitors and small interfering RNA (siRNA) against MLTK-alpha.

Main Results:

  • MLTK-alpha directly phosphorylates histone H3 at Ser28, but not Ser10.
  • MLTK-alpha's interaction with and phosphorylation of histone H3 are enhanced by UVB and EGF.
  • UVB/EGF-induced histone H3 Ser28 phosphorylation is dependent on MLTK-alpha and independent of MEK and p38 pathways.
  • MLTK-alpha knockdown blocks UVB/EGF-induced histone H3 Ser28 phosphorylation without affecting MSK1 or p90RSK activity.

Conclusions:

  • MLTK-alpha is a novel histone H3 kinase that phosphorylates Ser28.
  • MLTK-alpha plays a crucial role in UVB- and EGF-induced histone H3 Ser28 phosphorylation.
  • MLTK-alpha functions at the level of MAPK kinase kinases in the signaling pathway leading to histone H3 modification.

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