Flt3 mutation activates p21WAF1/CIP1 gene expression through the action of STAT5.
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.
Takahashi
Shinichiro
S
Division of Hematology/Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. shintak@mail.tains.tohoku.ac.jp
Harigae
Hideo
H
Kaku
Mitsuo
M
Sasaki
Takeshi
T
Licht
Jonathan D
JD
D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008894:Milk Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins; D051941:fms-Like Tyrosine Kinase 3
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3