A dual function for p38 MAP kinase in hematopoietic cells: involvement in apoptosis and cell activation

Leukemia. 1999 Jul;13(7):1037-45. doi: 10.1038/sj.leu.2401447.


In the present study we examined in more detail the dual role of the c-JUN N-terminal kinase (JNK) and p38 stress-activated protein kinase pathways in mediating apoptosis or cellular activation in hematopoietic cells. Growth factor deprivation of the erythroleukemic cell line TF-1 led to apoptosis which was associated with an enhanced activity of JNK and p38 and immediate dephosphorylation of the extracellular signal-regulated kinases (ERKs). Enhanced activity of p38 and JNK was not only observed during apoptosis but also in TF-1 cells stimulated with IL-1. IL-1 rescued TF-1 cells from apoptosis. In this case, the upregulation of p38 and JNK was associated with an enhanced activity of ERK. By using SB203580, a specific inhibitor of the p38 signaling pathway, it was demonstrated that p38 plays a pivotal role in the apoptotic process. SB203580 repressed the apoptotic process to a large extent. In contrast, PD98059, a specific inhibitor of the ERK pathway, counteracted the suppressive effects of SB203580 and IL-1 on the apoptotic process indicating that the protective effect of SB203580 and IL-1 might be the result of a shift in the balance between the ERK1/2 and p38/JNK route. This was also supported by experiments with TF-1 cells overexpressing the Shc protein that demonstrated a significantly lower percentage of apoptotic cells, which coincided with higher ERK activity. Finally, the IL-1 and SB203580-mediated effects were associated with an enhanced nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) binding activity, which could also be blocked by PD98059. These data demonstrate a dual function of the p38 pathway whereby other factors, such as ERK kinases, AP-1 and NF-kappaB, might determine the final cellular response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / physiology*
  • Calcium-Calmodulin-Dependent Protein Kinases / biosynthesis
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Survival / drug effects
  • Down-Regulation
  • Enzyme Activation
  • Enzyme Induction
  • Growth Substances / deficiency
  • Hematopoietic Stem Cells / enzymology*
  • Humans
  • Interleukin-1 / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Leukemia, Erythroblastic, Acute / enzymology
  • Leukemia, Erythroblastic, Acute / pathology
  • Mitogen-Activated Protein Kinases*
  • Tumor Cells, Cultured
  • p38 Mitogen-Activated Protein Kinases


  • Growth Substances
  • Interleukin-1
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases