Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis
| Autor: | Steffi Graf, Ulrich Keller, Jonas Nilsson, Christian Peschel, Lisa Nilsson, Jennifer B Old, John L. Cleveland, Alexander Hoellein, Susanne Kratzat, Keiichi I. Nakayama |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Lymphoma B-Cell medicine.disease_cause Article Proto-Oncogene Proteins c-myc Mice Cyclin-dependent kinase SKP2 medicine CDC2-CDC28 Kinases Tumor Cells Cultured Animals Humans Molecular Biology S-Phase Kinase-Associated Proteins Cells Cultured Cyclin Cell Proliferation Mice Knockout biology Kinase Tumor Suppressor Proteins Intracellular Signaling Peptides and Proteins Cyclin-Dependent Kinases Ubiquitin ligase Up-Regulation Gene Expression Regulation Neoplastic Mice Inbred C57BL Cell Transformation Neoplastic Oncology biology.protein Cancer research Phosphorylation Carcinogenesis Carrier Proteins Cyclin-Dependent Kinase Inhibitor p27 |
| Popis: | The universal cyclin-dependent kinase inhibitor p27Kip1 functions as a tumor suppressor, and reduced levels of p27Kip1 connote poor prognosis in several human malignancies. p27Kip1 levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCFSkp2 complex following its phosphorylation by the cyclin E–cyclin-dependent kinase 2 complex. Binding of phospho-p27Kip1 is directed by the Skp2 F-box protein, and this is greatly augmented by its allosteric regulator Cks1. We have established that programmed expression of c-Myc in the B cells of Eμ-Myc transgenic mice triggers p27Kip1 destruction by inducing Cks1, that this response controls Myc-driven proliferation, and that loss of Cks1 markedly delays Myc-induced lymphomagenesis and cancels the dissemination of these tumors. Here, we report that elevated levels of Skp2 are a characteristic of Eμ-Myc lymphomas and of human Burkitt lymphoma that bear MYC/Immunoglobulin chromosomal translocations. As expected, Myc-mediated suppression of p27Kip1 was abolished in Skp2-null Eμ-Myc B cells. However, the effect of Skp2 loss on Myc-driven proliferation and lymphomagenesis was surprisingly modest compared with the effects of Cks1 loss. Collectively, these findings suggest that Cks1 targets, in addition to p27Kip1, are critical for Myc-driven proliferation and tumorigenesis. Mol Cancer Res; 8(3); 353–62 |
| Databáze: | OpenAIRE |
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