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

被引:56
作者
Birkenkamp, KU
Dokter, WHA
Esselink, MT
Jonk, LJC
Kruijer, W
Vellenga, E
机构
[1] Univ Groningen, Dept Med, Div Hematol, NL-9700 AB Groningen, Netherlands
[2] Univ Groningen, Dept Med, Ctr Biomed Technol, NL-9700 AB Groningen, Netherlands
[3] Univ Groningen, Dept Biol, Div Dev Genet, NL-9700 AB Groningen, Netherlands
关键词
p38 MAP kinase; ERK kinase; apoptosis; cell activation;
D O I
10.1038/sj.leu.2401447
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:1037 / 1045
页数:9
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