Proto-oncogene c-jun expression is induced by AML1-ETO in a JNK dependent manner:possible role in the pathogenesis of acute myeloid leukemia
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vor 20 Jahren
Overexpression of proto-oncogene c-jun and constitutive activation
of the Jun NH2-terminal kinase (JNK) signaling pathway have been
implicated in the leukemic transformation process. However, c-jun
expression has not been investigated in acute myeloid leukemia
(AML) cells containing the most common chromosomal translocations.
t(8;21) is one of the most common AML-associated translocation and
results in the AML1-ETO fusion protein. Overexpression of AML1-ETO
in NIH3T3 cells leads to increased phosphorylation of Ser63 in
c-Jun, which is generally JNK dependent. The role of the JNK
signaling pathway for the functional properties of AML1-ETO is,
however, unknown. In the present study we found high expression
levels of c-jun mRNA in t(8;21), t(15;17) or inv(16) positive
patient cells by microarray analysis. Within t(8;21) positive
patient samples, there was a correlation between AML1-ETO and c-jun
mRNA expression levels. In myeloid U937 cells, c-jun mRNA and c-Jun
protein expression levels increased upon induction of AML1-ETO.
AML1-ETO transactivated the human c-jun promoter through the
proximal AP-1 site via activating the JNK signaling pathway. JNK
targets c-Jun and ATF-2, which also bind to the proximal AP-1 site
in U937 cells, were also phosphorylated upon AML1-ETO induction.
Furthermore, AML1-ETO induction increased the DNA binding capacity
of c-Jun and ATF-2 to the proximal AP-1 site of the c-jun promoter,
which might result in their enhanced transactivation capacities.
Interference with JNK and c-Jun activation by using JIP-1 or a JNK
inhibitor reduced the transactivation capacity of AML1-ETO on the
c-jun promoter and the pro-apoptotic function of AML1-ETO in U937
cells. AML1-ETO seems to activate the JNK signaling pathway by
inducing the expression of a cytoplasmic factor, possibly G-CSF,
because supernatant of AML1-ETO expressing cells was sufficient to
induce phosphorylation of JNK and c-Jun in wildtype U937 cells.
This data demonstrates a novel mechanism of how AML1-ETO might
exert positive effects on target gene expression and identifies the
proto-oncogene c-jun as a common target gene in AML patient cells.
of the Jun NH2-terminal kinase (JNK) signaling pathway have been
implicated in the leukemic transformation process. However, c-jun
expression has not been investigated in acute myeloid leukemia
(AML) cells containing the most common chromosomal translocations.
t(8;21) is one of the most common AML-associated translocation and
results in the AML1-ETO fusion protein. Overexpression of AML1-ETO
in NIH3T3 cells leads to increased phosphorylation of Ser63 in
c-Jun, which is generally JNK dependent. The role of the JNK
signaling pathway for the functional properties of AML1-ETO is,
however, unknown. In the present study we found high expression
levels of c-jun mRNA in t(8;21), t(15;17) or inv(16) positive
patient cells by microarray analysis. Within t(8;21) positive
patient samples, there was a correlation between AML1-ETO and c-jun
mRNA expression levels. In myeloid U937 cells, c-jun mRNA and c-Jun
protein expression levels increased upon induction of AML1-ETO.
AML1-ETO transactivated the human c-jun promoter through the
proximal AP-1 site via activating the JNK signaling pathway. JNK
targets c-Jun and ATF-2, which also bind to the proximal AP-1 site
in U937 cells, were also phosphorylated upon AML1-ETO induction.
Furthermore, AML1-ETO induction increased the DNA binding capacity
of c-Jun and ATF-2 to the proximal AP-1 site of the c-jun promoter,
which might result in their enhanced transactivation capacities.
Interference with JNK and c-Jun activation by using JIP-1 or a JNK
inhibitor reduced the transactivation capacity of AML1-ETO on the
c-jun promoter and the pro-apoptotic function of AML1-ETO in U937
cells. AML1-ETO seems to activate the JNK signaling pathway by
inducing the expression of a cytoplasmic factor, possibly G-CSF,
because supernatant of AML1-ETO expressing cells was sufficient to
induce phosphorylation of JNK and c-Jun in wildtype U937 cells.
This data demonstrates a novel mechanism of how AML1-ETO might
exert positive effects on target gene expression and identifies the
proto-oncogene c-jun as a common target gene in AML patient cells.
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