Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis

Jennifer B. Old, Susanne Kratzat, Alexander Hoellein, Steffi Graf, Jonas A. Nilsson, Lisa Nilsson, Keiichi Nakayama, Christian Peschel, John L. Cleveland, Ulrich B. Keller

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Abstract

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 p27 Kip1 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.

Original languageEnglish
Pages (from-to)353-362
Number of pages10
JournalMolecular Cancer Research
Volume8
Issue number3
DOIs
Publication statusPublished - Mar 1 2010

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S-Phase Kinase-Associated Proteins
B-Lymphocytes
F-Box Proteins
Cyclin-Dependent Kinase 2
Cyclin E
Neoplasms
Genetic Translocation
Ubiquitin-Protein Ligases
Burkitt Lymphoma
Cyclin-Dependent Kinases
Ubiquitin
Transgenic Mice
Immunoglobulins
Lymphoma
Carcinogenesis
Phosphorylation
Proteins

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Old, J. B., Kratzat, S., Hoellein, A., Graf, S., Nilsson, J. A., Nilsson, L., ... Keller, U. B. (2010). Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis. Molecular Cancer Research, 8(3), 353-362. https://doi.org/10.1158/1541-7786.MCR-09-0232

Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis. / Old, Jennifer B.; Kratzat, Susanne; Hoellein, Alexander; Graf, Steffi; Nilsson, Jonas A.; Nilsson, Lisa; Nakayama, Keiichi; Peschel, Christian; Cleveland, John L.; Keller, Ulrich B.

In: Molecular Cancer Research, Vol. 8, No. 3, 01.03.2010, p. 353-362.

Research output: Contribution to journalArticle

Old, JB, Kratzat, S, Hoellein, A, Graf, S, Nilsson, JA, Nilsson, L, Nakayama, K, Peschel, C, Cleveland, JL & Keller, UB 2010, 'Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis', Molecular Cancer Research, vol. 8, no. 3, pp. 353-362. https://doi.org/10.1158/1541-7786.MCR-09-0232
Old, Jennifer B. ; Kratzat, Susanne ; Hoellein, Alexander ; Graf, Steffi ; Nilsson, Jonas A. ; Nilsson, Lisa ; Nakayama, Keiichi ; Peschel, Christian ; Cleveland, John L. ; Keller, Ulrich B. / Skp2 directs Myc-mediated suppression of p27Kip1 yet has modest effects on Myc-driven lymphomagenesis. In: Molecular Cancer Research. 2010 ; Vol. 8, No. 3. pp. 353-362.
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