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Skp2 directs myc-mediated suppression of p27(kip1) yet has modest effects on myc-driven lymphomagenesis

Academic Article
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Overview

authors

  • Old, J. B.
  • Kratzat, S.
  • Hoellein, A.
  • Graf, S.
  • Nilsson, J. A.
  • Nilsson, L.
  • Nakayama, K. I.
  • Peschel, C.
  • Cleveland, John
  • Keller, U. B.

publication date

  • March 2010

journal

  • Molecular Cancer Research  Journal

abstract

  • The universal cyclin-dependent kinase inhibitor p27(Kip1) functions as a tumor suppressor, and reduced levels of p27(Kip1) connote poor prognosis in several human malignancies. p27(Kip1) levels are predominately regulated by ubiquitin-mediated turnover of the protein, which is marked for destruction by the E3 ubiquitin ligase SCF(Skp2) complex following its phosphorylation by the cyclin E-cyclin-dependent kinase 2 complex. Binding of phospho-p27(Kip1) 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 Emu-Myc transgenic mice triggers p27(Kip1) 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 Emu-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 Emu-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 p27(Kip1), are critical for Myc-driven proliferation and tumorigenesis.

subject areas

  • Animals
  • CDC2-CDC28 Kinases
  • Carrier Proteins
  • Cell Proliferation
  • Cell Transformation, Neoplastic
  • Cells, Cultured
  • Cyclin-Dependent Kinase Inhibitor p27
  • Cyclin-Dependent Kinases
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Lymphoma, B-Cell
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Proto-Oncogene Proteins c-myc
  • S-Phase Kinase-Associated Proteins
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins
  • Up-Regulation
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Identity

PubMed Central ID

  • PMC3095030

International Standard Serial Number (ISSN)

  • 1541-7786

Digital Object Identifier (DOI)

  • 10.1158/1541-7786.mcr-09-0232

PubMed ID

  • 20197382
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Additional Document Info

start page

  • 353

end page

  • 362

volume

  • 8

issue

  • 3

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