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Inability to phosphorylate Y88 of p27Kip1enforces reduced p27 protein levels and accelerates leukemia progression

التفاصيل البيبلوغرافية
العنوان: Inability to phosphorylate Y88 of p27Kip1enforces reduced p27 protein levels and accelerates leukemia progression
المؤلفون: Jäkel, Heidelinde, Taschler, Martin, Jung, Karin, Weinl, Christina, Pegka, Fragka, Kullmann, Michael Keith, Podmirseg, Silvio Roland, Dutta, Sayantanee, Moser, Markus, Hengst, Ludger
المصدر: Leukemia; July 2022, Vol. 36 Issue: 7 p1916-1925, 10p
مستخلص: The cyclin-dependent kinase (CDK) inhibitor p27Kip1regulates cell proliferation. Phosphorylation of tyrosine residue 88 (Y88) converts the inhibitor into an assembly factor and activator of CDKs, since Y88-phosphorylation restores activity to cyclin E,A/CDK2 and enables assembly of active cyclin D/CDK4,6. To investigate the physiological significance of p27 tyrosine phosphorylation, we have generated a knock-in mouse model where Y88 was replaced by phenylalanine (p27-Y88F). Young p27-Y88F mice developed a moderately reduced body weight, indicative for robust CDK inhibition by p27-Y88F. When transformed with v-ABL or BCR::ABL1p190, primary p27-Y88F cells are refractory to initial transformation as evidenced by a diminished outgrowth of progenitor B-cell colonies. This indicates that p27-Y88 phosphorylation contributes to v-ABL and BCR::ABL1p190induced transformation. Surprisingly, p27-Y88F mice succumbed to premature v-ABL induced leukemia/lymphoma compared to p27 wild type animals. This was accompanied by a robust reduction of p27-Y88F levels in v-ABL transformed cells. Reduced p27-Y88F levels seem to be required for efficient cell proliferation and may subsequently support accelerated leukemia progression. The potent downregulation p27-Y88F levels in all leukemia-derived cells could uncover a novel mechanism in human oncogenesis, where reduced p27 levels are frequently observed.
قاعدة البيانات: Supplemental Index
الوصف
تدمد:08876924
14765551
DOI:10.1038/s41375-022-01598-x