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MEK guards proteome stability and inhibits tumor-suppressive amyloidogenesis via HSF1

Zijian Tang1, Siyuan Dai2, Yishu He2

  • 1The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA; Graduate Programs, Department of Molecular and Biomedical Sciences, The University of Maine, 5735 Hitchner Hall, Orono, ME 04469, USA.

Cell
|February 14, 2015
PubMed

Insights

The RAS/MAP kinase pathway

Area of Science:

  • Cellular Biology
  • Oncology
  • Proteostasis

Background:

  • The RAS/MAP kinase pathway is crucial in cell signaling.
  • ERK was previously considered the sole MEK substrate.
  • The role of MEK in regulating the proteotoxic stress response was unclear.

Purpose of the Study:

  • To identify novel MEK substrates.
  • To investigate the role of MEK-HSF1 signaling in cancer.
  • To explore therapeutic strategies targeting tumor proteostasis.

Main Methods:

  • Investigated MEK-HSF1 interaction and regulation.
  • Analyzed proteomic changes in tumor cells upon MEK blockade.
  • Assessed the impact of amyloidogenesis on tumor growth in vivo.

Main Results:

  • HSF1 identified as a novel MEK substrate.
  • MEK blockade in tumor cells causes proteomic chaos and amyloidogenesis.
  • Tumor cells exhibit heightened susceptibility to proteomic perturbation.
  • Amyloidogenesis demonstrates tumor-suppressive effects, inhibiting melanoma growth.

Conclusions:

  • Oncogenic RAS-MEK signaling maintains proteostasis and suppresses amyloidogenesis.
  • Proteomic instability is inherent to the malignant state.
  • Targeting tumor proteostasis to induce amyloidogenesis is a potential anti-cancer strategy.

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