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Mixed lineage kinase 3 (MLK3)-activated p38 MAP kinase mediates transforming growth factor-beta-induced apoptosis in

Ki-Yong Kim1, Byung-Chul Kim, Zhiheng Xu

  • 1Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892, USA.

The Journal of Biological Chemistry
|April 8, 2004
PubMed

Insights

Transforming growth factor beta1 (TGF-beta1) triggers cell death through mixed lineage kinases (MLKs) and p38 MAP kinase pathways in hepatoma cells, revealing new therapeutic targets.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Transforming growth factor beta1 (TGF-beta1) signaling regulates gene transcription via Smad pathways.
  • The role of TGF-beta1-induced mitogen-activated protein kinase (MAPK) kinase activation in apoptosis is not fully understood.
  • p38 MAPK and c-Jun NH2-terminal kinases (JNKs) are implicated in TGF-beta1-induced hepatoma cell death, but upstream regulators are undefined.

Purpose of the Study:

  • To investigate the role of mixed lineage kinases (MLKs) in TGF-beta1-induced apoptosis in hepatoma cells.
  • To identify upstream mediators of p38 and JNK activation in TGF-beta1 signaling.
  • To elucidate the involvement of MLKs in the TGF-beta1 death signaling pathway.

Main Methods:

  • Expression analysis of MLK family members (MLK1, MLK2, MLK3, DLK) in FaO rat hepatoma cells.
  • Assessment of MLK3 activity following TGF-beta1 treatment.
  • Manipulation of MLK expression (overexpression and dominant-negative forms) to study effects on TGF-beta1-induced apoptosis and MAPK activation.
  • Inhibition of the p38 pathway to determine its role in TGF-beta1-induced apoptosis.

Main Results:

  • MLK family members are expressed in hepatoma cells and likely function upstream of p38 in TGF-beta1 death signaling.
  • TGF-beta1 increases MLK3 activity, and MLK3 overexpression enhances TGF-beta1-induced apoptosis.
  • Dominant-negative MLK forms suppress TGF-beta1-induced cell death and MAPK activation (ERK, JNKs, p38).
  • Only p38 pathway inhibition effectively suppressed TGF-beta1-induced apoptosis.

Conclusions:

  • Mixed lineage kinases (MLKs) play a crucial role in mediating TGF-beta1-induced apoptosis in hepatoma cells.
  • MLKs act upstream of p38 and JNK pathways in the TGF-beta1 death signaling cascade.
  • Targeting MLKs or the p38 pathway may offer therapeutic strategies for TGF-beta1-related conditions.

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