A dual function for p38 MAP kinase in hematopoietic cells: involvement in apoptosis and cell activation.
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.
Department of Medicine, University of Groningen, The Netherlands.
K U
KU
Birkenkamp
W H
WH
Dokter
M T
MT
Esselink
L J
LJ
Jonk
W
W
Kruijer
E
E
Vellenga
D017209:Apoptosis / Q000502:physiology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000096:biosynthesis / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D004789:Enzyme Activation; D004790:Enzyme Induction; D006133:Growth Substances / Q000172:deficiency; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D004915:Leukemia, Erythroblastic, Acute / Q000201:enzymology / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D006133:Growth Substances; D007375:Interleukin-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases