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首页> 美国政府科技报告 >Elucidating the Mechanism of p27 Inactivation by the Bcr-Abl Tyrosine Kinase.
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Elucidating the Mechanism of p27 Inactivation by the Bcr-Abl Tyrosine Kinase.

机译：阐明Bcr-abl酪氨酸激酶对p27失活的作用机制。

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Inhibition of Bcr-Abl kinase activity in Mo7e P210BCR-ABLcells induces accumulation of cells in G0/1. This is associated with (a) increased total levels of p27, (b) accumulation of p27 in the nucleus but not the cytoplasm, and (c) decrease of nuclear but not cytoplasmic Cdk2 /cylin E kinase activity. Despite the decrease of Cdk2/cyclin E activity, most of the nuclear p27 is phosphorylated on threonine 187, consistent with diminished nuclear degradation. In accordance with this, the expression of KPC (subunit 1 and 2), the ubiquitin ligase responsible for targeting cytoplasmic p27 for degradation, was not affected by inhibition of Bcr-Abl. The reduced degradation of nuclear p27 is likely due to down regulation of Skp2, the F-box protein of the SCFSKP2 complex that specifically recognizes T187 phosphorylated p27 and targets it for proteasomal degradation. Although no major differences in lineage marker expression were seen in Skp2 knockout mice compared to wild type mice, there appears to have reduced clonogenicity in response to growth factors and upon expression of Bcr-Abl. This may lead to reduced leukomogenicity of Bcr-Abl in a Skp2 -/- background.

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