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V-jun overrides the mitogen dependence of s-phase entry by deregulating retinoblastoma protein phosphorylation and e2f-pocket protein interactions as a consequence of enhanced cyclin e-cdk2 catalytic activity

Academic Article
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Overview

authors

  • Clark, W.
  • Black, E. J.
  • MacLaren, A.
  • Kruse, U.
  • LaThangue, N.
  • Vogt, Peter K.
  • Gillespie, D. A. F.

publication date

  • April 2000

journal

  • Molecular and Cellular Biology  Journal

abstract

  • v-Jun accelerates G(1) progression and shares the capacity of the Myc, E2F, and E1A oncoproteins to sustain S-phase entry in the absence of mitogens; however, how it does so is unknown. To gain insight into the mechanism, we investigated how v-Jun affects mitogen-dependent processes which control the G(1)/S transition. We show that v-Jun enables cells to express cyclin A and cyclin A-cdk2 kinase activity in the absence of growth factors and that deregulation of cdk2 is required for S-phase entry. Cyclin A expression is repressed in quiescent cells by E2F acting in conjunction with its pocket protein partners Rb, p107, and p130; however, v-Jun overrides this control, causing phosphorylated Rb and proliferation-specific E2F-p107 complexes to persist after mitogen withdrawal. Dephosphorylation of Rb and destruction of cyclin A nevertheless occur normally at mitosis, indicating that v-Jun enables cells to rephosphorylate Rb and reaccumulate cyclin A without exogenous mitogenic stimulation each time the mitotic "clock" is reset. D-cyclin-cdk activity is required for Rb phosphorylation in v-Jun-transformed cells, since ectopic expression of the cdk4- and cdk6-specific inhibitor p16(INK4A) inhibits both DNA synthesis and cell proliferation. Despite this, v-Jun does not stimulate D-cyclin-cdk activity but does induce a marked deregulation of cyclin E-cdk2. In particular, hormonal activation of a conditional v-Jun-estrogen receptor fusion protein in quiescent, growth factor-deprived cells stimulates cyclin E-cdk2 activity and triggers Rb phosphorylation and DNA synthesis. Thus, v-Jun overrides the mitogen dependence of S-phase entry by deregulating Rb phosphorylation, E2F-pocket protein interactions, and ultimately cyclin A-cdk2 activity. This is the first report, however, that cyclin E-cdk2, rather than D-cyclin-cdk, is likely to be the critical Rb kinase target of v-Jun.

subject areas

  • Animals
  • CDC2-CDC28 Kinases
  • Carrier Proteins
  • Cell Cycle
  • Cell Division
  • Chick Embryo
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinases
  • Cyclins
  • Fibroblasts
  • G1 Phase
  • Microinjections
  • Mitogens
  • Oncogene Protein p65(gag-jun)
  • Oncogene Proteins
  • Phosphorylation
  • Plasmids
  • Protein Serine-Threonine Kinases
  • Retinoblastoma Protein
  • S Phase
  • Transformation, Genetic
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Identity

PubMed Central ID

  • PMC85463

International Standard Serial Number (ISSN)

  • 0270-7306

Digital Object Identifier (DOI)

  • 10.1128/mcb.20.7.2529-2542.2000

PubMed ID

  • 10713176
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Additional Document Info

start page

  • 2529

end page

  • 2542

volume

  • 20

issue

  • 7

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