期刊
LEUKEMIA
卷 36, 期 7, 页码 1916-1925出版社
SPRINGERNATURE
DOI: 10.1038/s41375-022-01598-x
关键词
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资金
- Austrian Science Fund (FWF) [P24031, W11]
- Austrian Cancer Aid/Tirol [16005]
- Austrian Science Fund (FWF) [P24031, W11] Funding Source: Austrian Science Fund (FWF)
The study reveals the importance of p27 tyrosine phosphorylation in v-ABL and BCR::ABL1(p190)-induced transformation. Surprisingly, p27-Y88F mice are more susceptible to v-ABL-induced leukemia/lymphoma, possibly due to a robust reduction of p27-Y88F levels leading to enhanced cell proliferation and accelerated leukemia progression.
The cyclin-dependent kinase (CDK) inhibitor p27(Kip1) regulates 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::ABL1(p190), 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::ABL1(p190) induced 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.
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