Role of acid/base hormeostasis in the suppression of apoptosis in haemopoietic cells by v-Abl protein tyrosine kinase

Quan Chen, Rod S.P. Benson, Anthony D. Whetton, Steven R. Brant, Mark Donowitz, Marshall H. Montrose, Caroline Dive, Alastair J.M. Watson

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Removal of interleukin-3 from murine IC.DP pre-mast cells results in irreversible commitment to apoptosis within 18 hours. To identify early events necessary for the engagement of apoptosis we examined the regulation of intracellular pH (pH(i)). IC.DP cells acidified 2 hours after removal of interleukin-3 (before discernible signs of apoptosis) and by 18 hours pH(i) had decreased by 0.15 units. The acidification was due to both an increase in an acid-loading process which only occurs when intracellular pH is above 6.8 and a slight reduction in H+ efflux via Na+/H+ exchange. Activation of a temperature sensitive mutant of v-Abl protein tyrosine kinase suppressed apoptosis of IC.DP cells in the absence of interleukin-3 but did not stimulate proliferation, and moreover prevented cellular acidification. Acidification of the cells by 0.2 units to pH 6.86 by complete inhibition of Na+/H+ exchange by 10 μM 5'-(N-methyl-N-isobutyl)-amiloride prevented the suppression of apoptosis by v-abl protein tyrosine kinase following IL 3 withdrawal. However in the presence of interleukin-3, addition of 10 μM 5'-(N-methyl-N-isobutyl)-amiloride only resulted in a fall of pH(i) to 7.17. Apoptosis did not occur and the cells continued to proliferate. Thus, in this model intracellular pH must fall below a critical value for apoptosis to occur. Together these data point to a step in cytokine deprivation induced apoptosis (at least in some haemopoietic cell types) which is either enhanced by or dependent upon an acidic intracellular environment which is the result of an increase in acid loading and inhibition of Na+/H+ exchange activity. One of the mechanisms by which activation of v-Abl protein tyrosine kinase suppresses apoptosis is by prevention of intracellular acidification.

Original languageEnglish (US)
Pages (from-to)379-387
Number of pages9
JournalJournal of cell science
Issue number3
StatePublished - Feb 1997
Externally publishedYes


  • Apoptosis
  • Interleukin-3
  • Intracellular pH
  • Sodium hydrogen exchange
  • V-Abl protein tyrosine kinase

ASJC Scopus subject areas

  • Cell Biology


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