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Kit signaling inhibits the sphingomyelin-ceramide pathway through PLC gamma 1: implication in stem cell factor

Stéphane Maddens1, Alexandra Charruyer, Isabelle Plo

  • 1Institut Nationale de la Santé et de la Recherche Médicale E9910, Institut Claudius Régaud, Toulouse, France.

Blood
|August 1, 2002
PubMed

Insights

Stem cell factor (SCF) protects against radiation by inhibiting ceramide production via phospholipase C gamma 1 (PLC gamma 1), not PI3K/Akt. This mechanism regulates cellular response to DNA damage.

Area of Science:

  • Cellular and Molecular Biology
  • Radiation Biology
  • Signal Transduction

Background:

  • Kit activation is known to confer radioprotection, but the underlying molecular mechanisms remain unclear.
  • The sphingomyelin (SM) cycle and ceramide production are implicated in ionizing radiation (IR)-induced apoptosis.
  • This study investigates how Kit signaling modulates the SM cycle and cellular response to IR.

Purpose of the Study:

  • To elucidate the mechanism by which Kit signaling confers radioprotection against ionizing radiation.
  • To determine if Kit signaling interferes with IR-induced ceramide production or apoptosis.
  • To identify the specific signaling pathway involved in Kit-mediated radioprotection.

Main Methods:

  • Utilized Ba/F3 and 32D murine cell lines expressing wild-type c-kit or mutated forms.
  • Investigated the effects of stem cell factor (SCF) stimulation on IR-induced apoptosis, cytotoxicity, and DNA repair.
  • Assessed neutral sphingomyelinase (N-SMase) activity and ceramide production.
  • Employed inhibitors for phosphoinositide-3 kinase (PI3K) and phospholipase C gamma (PLC gamma).
  • Tested radioprotection in human CD34(+) bone marrow cells.

Main Results:

  • SCF stimulation significantly reduced IR-induced apoptosis and cytotoxicity without affecting DNA repair.
  • SCF inhibited IR-induced N-SMase activation and ceramide production.
  • The radioprotective effect of SCF was independent of PI3K/Akt signaling but dependent on PLC gamma 1.
  • Inhibition of PLC gamma 1 abolished SCF-mediated radioprotection in both cell lines and human bone marrow cells.
  • SCF did not protect cells lacking a functional PLC gamma 1 docking site.

Conclusions:

  • Stem cell factor (SCF) confers radioprotection primarily through the PLC gamma 1-dependent inhibition of IR-induced N-SMase stimulation and subsequent ceramide production.
  • The PI3K/Akt pathway is not involved in SCF-mediated radioprotection.
  • PLC gamma 1 plays a crucial role in modulating cellular responses to DNA damage induced by ionizing radiation.
  • These findings suggest that PLC gamma 1 status may influence sensitivity to genotoxic agents beyond Kit-expressing cells.

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