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

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An essential role for mitogen-activated protein kinases, ERKs, in preventing heat-induced cell death

W Woessmann1, Y H Meng, N F Mivechi

  • 1Medical College of Georgia, Augusta, Georgia 30912, USA.

Journal of Cellular Biochemistry
|August 10, 1999
PubMed

Insights

Heat shock activates mitogen-activated protein kinases (MAPKs) via ceramide metabolism, unlike irradiation. This pathway is absent in leukemic cells, increasing their heat sensitivity.

Area of Science:

  • Cellular stress response
  • Signal transduction pathways
  • Cancer biology

Background:

  • Mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated protein kinases (ERKs), are activated by UV and X-irradiation through receptor tyrosine kinases and the Ras/Raf/Mek/ERKs cascade.
  • MAPK activation is implicated in repairing damaged proteins following irradiation stress.
  • The signaling pathways and downstream effects of heat shock-induced MAPK activation remain largely uncharacterized.

Purpose of the Study:

  • To elucidate the signaling cascade by which heat shock activates MAPKs.
  • To investigate the differential activation of MAPKs by heat in various cell types, particularly comparing normal fibroblasts and myeloid leukemic cells.
  • To determine the role of heat-induced MAPK activation in cellular thermotolerance and its implications for cancer therapy.

Main Methods:

  • Investigated heat-induced MAPK activation using ceramide metabolism and sphingosine signaling.
  • Utilized myeloid leukemic cell lines (HL-60, U937, K562) and NIH3T3 fibroblasts to assess cell-type specific signaling.
  • Employed stable overexpression of dominant-negative (ERK1-KR) and wild-type ERK1 alleles to modulate MAPK activity and assess heat sensitivity.

Main Results:

  • Heat shock activates MAPKs through ceramide metabolism to sphingosine, stimulating Raf-1 protein kinase, a mechanism distinct from irradiation-induced activation.
  • MAPK activation by heat is cell-type specific; the pathway is deficient in myeloid leukemic cells but present in NIH3T3 fibroblasts.
  • Overexpression of dominant-negative ERK1-KR increased heat sensitivity up to 100-fold in NIH3T3 and K562 cells, while wild-type ERK1 overexpression conferred heat resistance.

Conclusions:

  • Heat shock activates MAPKs via a novel ceramide-dependent pathway involving sphingosine and Raf-1, differing from irradiation-induced signaling.
  • The absence of this pathway in leukemic cells suggests a potential mechanism for their increased sensitivity to thermal stress.
  • Modulating MAPK activity impacts cellular survival during heat shock, indicating therapeutic potential for targeting this pathway in cancer treatment.

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