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

KU Birkenkamp, WHA Dokter, MT Esselink, LJC Jonk, W Kruijer, E Vellenga*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

58 Citations (Scopus)

Abstract

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-kappa B (NF-kappa B) 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-kappa B, might determine the final cellular response.

Original languageEnglish
Pages (from-to)1037-1045
Number of pages9
JournalLeukemia
Volume13
Issue number7
Publication statusPublished - Jul-1999

Keywords

  • p38 MAP kinase
  • ERK kinase
  • apoptosis
  • cell activation
  • SIGNAL-TRANSDUCTION PATHWAY
  • TRANSCRIPTION FACTOR AP-1
  • TUMOR-NECROSIS-FACTOR
  • NF-KAPPA-B
  • PROTEIN-KINASE
  • C-JUN
  • GROWTH-FACTORS
  • JNK ACTIVATION
  • STRESS
  • RECEPTOR

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