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Blood, Vol. 94 No. 12 (December 15), 1999:
pp. 4067-4076
Distinct Roles of JNKs/p38 MAP Kinase and ERKs in Apoptosis and
Survival of HCD-57 Cells Induced by Withdrawal or Addition of
Erythropoietin
Rujiao Shan,
James O. Price,
William A. Gaarde,
Brett P. Monia,
Sanford B. Krantz, and
Zhizhuang Joe Zhao
From the Division of Hematology/Oncology, Department of Medicine,
Department of Pathology, Department of Veterans Affairs Medical
Service, and Vanderbilt-Ingram Cancer Center, Vanderbilt University,
Nashville, TN; and the Department of Molecular Pharmacology, Isis
Pharmaceuticals, Carlsbad, CA.
Erythropoietin (EPO), a major regulator of erythroid progenitor
cells, is essential for the survival, proliferation, and
differentiation of immature erythroid cells. To gain insight into the
molecular mechanism by which EPO functions, we analyzed the activation
of Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs) in HCD-57 cells, a murine erythroid progenitor cell line
that requires EPO for survival and proliferation. Withdrawal of EPO
from the cell culture medium resulted in sustained activation of JNKs
plus p38 MAP kinase, and inactivation of ERKs, preceding apoptosis of
the cells. Addition of EPO to the EPO-deprived cells caused activation
of ERKs accompanied by inactivation of JNKs and p38 MAP kinase and
rescued the cells from apoptosis. Phorbol 12-myristate 13-acetate,
which activated ERKs by a different mechanism, also suppressed the
activation of JNKs and significantly retarded apoptosis of the cells
caused by withdrawal of EPO. Furthermore, MEK inhibitor PD98059, which
inhibited activation of ERKs, caused activation of JNKs, whereas
suppression of JNK expression by antisense oligonucleotides and
inhibition of p38 MAP kinase by SB203580 caused attenuation of the
apoptosis that occurs upon withdrawal of EPO. Finally, the activation
of JNKs and p38 MAP kinase and concurrent inactivation of ERKs upon
withdrawal of EPO were also observed in primary human erythroid
colony-forming cells. Taken together, the data suggest that activation
of ERKs promotes cell survival, whereas activation of JNKs and p38 MAP
kinase leads to apoptosis and EPO functions by controlling the dynamic
balance between ERKs and JNKs.
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