Inability to phosphorylate Y88 of p27(Kip1) enforces reduced p27 protein levels 
and accelerates leukemia progression

Jakel, H.; Taschler, M.; Jung, Karin; Weinl, C.; Pegka, F.; Kullmann, M. K.; Podmirseg, S. R.; Dutta, Sayantanee; Moser, M.; Hengst, Ludger

doi:10.1038/s41375-022-01598-x

Item

ITEM ACTIONSEXPORT

Add to Basket

Local TagsRelease HistoryDetailsSummary

Released

Journal Article

Inability to phosphorylate Y88 of p27(Kip1) enforces reduced p27 protein levels and accelerates leukemia progression

MPS-Authors

/persons/resource/persons78420

Moser, M.
Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

There is no public supplementary material available

Citation

Jakel, H., Taschler, M., Jung, K., Weinl, C., Pegka, F., Kullmann, M. K., et al. (2022). Inability to phosphorylate Y88 of p27(Kip1) enforces reduced p27 protein levels and accelerates leukemia progression. Leukemia, 36, 1916-1925. doi:10.1038/s41375-022-01598-x.

Cite as: https://hdl.handle.net/21.11116/0000-000A-A3E2-E

Abstract

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.