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Blood, Vol. 93 No. 11 (June 1), 1999:
pp. 3893-3899
Constitutive Activation of Extracellular Signal-Regulated Kinase in
Human Acute Leukemias: Combined Role of Activation of MEK,
Hyperexpression of Extracellular Signal-Regulated Kinase, and
Downregulation of a Phosphatase, PAC1
Seong-Cheol Kim,
Jee-Sook Hahn,
Yoo-Hong Min,
Nae-Choon Yoo,
Yun-Woong Ko, and
Won-Jae Lee
From the Department of Internal Medicine and Laboratory of
Immunology, Medical Research Center, Yonsei University College of
Medicine, Seoul, Korea.
Extracellular signal-regulated kinase (ERK) is an important
intermediate in signal transduction pathways that are initiated by many
types of cell surface receptors. It is thought to play a pivotal role
in integrating and transmitting transmembrane signals required for
growth and differentiation. Constitutive activation of ERK in
fibroblasts elicits oncogenic transformation, and recently, constitutive activation of ERK has been observed in some human malignancies, including acute leukemia. However, mechanisms underlying constitutive activation of ERK have not been well characterized. In
this study, we examined the activation of ERK in 79 human acute leukemia samples and attempted to find factors contributing to constitutive ERK activation. First, we showed that ERK and MEK were
constitutively activated in acute leukemias by in vitro kinase assay
and immunoblot analysis. However, in only one half of the studied
samples, the pattern of ERK activation was similar to that of MEK
activation. Next, by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblot analysis, we showed
hyperexpression of ERK in a majority of acute leukemias. In 17 of 26 cases (65.4%) analyzed by immunoblot, the pattern of ERK expression
was similar to that of ERK activation. The fact of constitutive
activation of ERK in acute leukemias suggested to us the possibility of
an abnormal downregulation mechanism of ERK. Therefore, we examined PAC1, a specific ERK phosphatase predominantly expressed in
hematopoietic tissue and known to be upregulated at the transcription
level in response to ERK activation. Interestingly, in our study, PAC1 gene expression in acute leukemias showing constitutive ERK activation was significantly lower than that in unstimulated, normal bone marrow
(BM) samples showing minimal or no ERK activation (P = .002).
Also, a significant correlation was observed between PAC1 downregulation and phosphorylation of ERK in acute leukemias (P = .002). Finally, by further analysis of 26 cases, we showed that a
complementary role of MEK activation, ERK hyperexpression, and PAC1
downregulation could contribute to determining the constitutive activation of ERK in acute leukemia. Our results suggest that ERK is
constitutively activated in a majority of acute leukemias, and in
addition to the activation of MEK, the hyperexpression of ERK and
downregulation of PAC1 also contribute to constitutive ERK activation
in acute leukemias.
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