Flt3 mutation activates p21WAF1/CIP1 gene expression through the action of STAT5
S Takahashi, H Harigae, M Kaku, T Sasaki… - … and biophysical research …, 2004 - Elsevier
S Takahashi, H Harigae, M Kaku, T Sasaki, JD Licht
Biochemical and biophysical research communications, 2004•ElsevierFlt3 is a type III RTK and approximately 30% of AML patients harbor an internal tandem
duplication (ITD) of the juxtamembrane region or a point mutation of the Flt3 protein leading
to the constitutive activation of downstream signaling pathways and aberrant cell growth.
The cyclin-dependent kinase inhibitor p21 inhibits cell growth when expressed at high levels
and induces cell growth when expressed at lower levels. In this study, we have addressed
the role of Flt3-ITD in the regulation of p21. Co-transfection of p21 promoter-luciferase …
duplication (ITD) of the juxtamembrane region or a point mutation of the Flt3 protein leading
to the constitutive activation of downstream signaling pathways and aberrant cell growth.
The cyclin-dependent kinase inhibitor p21 inhibits cell growth when expressed at high levels
and induces cell growth when expressed at lower levels. In this study, we have addressed
the role of Flt3-ITD in the regulation of p21. Co-transfection of p21 promoter-luciferase …
Flt3 is a type III RTK and approximately 30% of AML patients harbor an internal tandem duplication (ITD) of the juxtamembrane region or a point mutation of the Flt3 protein leading to the constitutive activation of downstream signaling pathways and aberrant cell growth. The cyclin-dependent kinase inhibitor p21 inhibits cell growth when expressed at high levels and induces cell growth when expressed at lower levels. In this study, we have addressed the role of Flt3-ITD in the regulation of p21. Co-transfection of p21 promoter-luciferase constructs with Flt3-ITD plasmid into K562 and BaF3 cells results in the induction of p21 promoter activity and a −692/−684 STAT site is important for the induction. STAT5a binds specifically to this element and Flt3-ITD enhances the protein binding to this site. Overexpression of Flt3-ITD led to the induction of endogenous p21 expression in various cells. These results may implicate p21 in Flt3-ITD induced leukemogenesis.
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