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

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.

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 Creators:
Jakel, H., Author
Taschler, M., Author
Jung, Karin, Author
Weinl, C., Author
Pegka, F., Author
Kullmann, M. K., Author
Podmirseg, S. R., Author
Dutta, Sayantanee, Author
Moser, M.1, Author           
Hengst, Ludger, Author
Affiliations:
1Fässler, Reinhard / Molecular Medicine, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565147              

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Free keywords: cell-cycle tyrosine phosphorylation mice lacking v-abl cancer transformation stability tumorigenesis hyperplasia inhibition Oncology Hematology
 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.

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Language(s): eng - English
 Dates: 2022-05-21
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: Other: WOS:000799682400001
DOI: 10.1038/s41375-022-01598-x
ISSN: 0887-6924
 Degree: -

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Title: Leukemia
  Other : Leukemia (Online-Ausg.)
Source Genre: Journal
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Affiliations:
Publ. Info: Basingstoke : Nature Publ. Group
Pages: - Volume / Issue: 36 Sequence Number: - Start / End Page: 1916 - 1925 Identifier: ISSN: 1476-5551
ISSN: 0887-6924
CoNE: https://pure.mpg.de/cone/journals/resource/954925554401