Cell cycle start from quiescence controlled by tyrosine phosphorylation of Cdk4

Jinno, Shigeki; Hung, Shih-Chieh; Okayama, Hiroto

doi:10.1038/sj.onc.1202347

Cited by 45 publications

(54 citation statements)

References 29 publications

(28 reference statements)

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“…CAK is generally considered to be constitutively active during cell cycle [37], but this should be demonstrated in our system. Very recently, the inhibitory tyrosine phosphorylation of CDK4 has been reported to be involved not only in DNA damage-induced G1 arrest, but also in regular cell's arrest in quiescence [38]. However, using the PY20 antibody we failed to detect the presence of phosphotyrosine in CDK4 immunoprecipitates of quiescent dog thyrocytes (negative data not shown).…”

Section: Discussionmentioning

confidence: 74%

Nature of the Critical Labile Event That Controls RB Phosphorylation in the Cyclic AMP-Dependent Cell Cycle of Thyrocytes in Primary Culture

Roger

Demartin

Dumont

1999

Experimental Cell Research

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This study addresses the nature of the critical labile event that couples at restriction point mitogenic cascades with the autonomous part of the cell cycle. In primary cultures of dog thyroid epithelial cells, kinetic experiments indicate that a labile cAMP-dependent event positively controls a late G1 commitment to DNA replication and RB phosphorylation. As previously shown in this system, the cAMP-dependent mitogenic pathway differs from the most generally envisaged growth factor cascades as it stimulates the accumulation of p27 kip1 but not of cyclins D. Nevertheless, cyclin D3 and CDK4 activity are essential in the cAMP-dependent mitogenesis, and cAMP unmasks the DCS-22 epitope of cyclin D3 and induces the nuclear translocations and assembly of cyclin D3 and CDK4 in a complex that also contains p27 kip1 . Unexpectedly, the washing out of forskolin rapidly arrested S phase entry and the accumulation of hyperphosphorylated RB, but did not reverse any of the above events associated with cyclin D3-CDK4 activation. This implies that even after induction of stable nuclear cyclin D3-CDK4 complexes, dog thyrocytes still depend on cAMP for RB phosphorylation and commitment to DNA synthesis, which suggests that a key labile event responsible for a last control of restriction point passage remains to be uncovered, in the cAMP-dependent cell cycle of dog thyrocytes and possibly other systems.

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Section: Discussionmentioning

confidence: 74%

Nature of the Critical Labile Event That Controls RB Phosphorylation in the Cyclic AMP-Dependent Cell Cycle of Thyrocytes in Primary Culture

Roger

Demartin

Dumont

1999

Experimental Cell Research

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“…This is in contrast to stimulation of Kit-225 cells by IL-2, which increased the steady-state levels of CDK4 mRNA by ϳ4-fold. Small increases in CDK4 protein were observed in Kit-225 cells stimulated by IL-2 for 1-3 h, but CDK4 activity increased by ϳ2-to 8-fold, suggesting IL-2 mediates additional events required for assembly and activation of active holoenzyme complexes (31,33). CDK4 activity was essentially abrogated in Kit-225 cells treated with anti-CD3, PHA, or PMA, and it could only be partially rescued by IL-2.…”

Section: Discussionmentioning

confidence: 95%

“…A critical role for CDK4 in cell cycle entry and the early stages of progression through the G 1 phase have been demonstrated in various cultured cell lines (31,32). However, it is generally believed that a growth factor signal is required to promote assembly and activation of active CDK4 complexes (33)(34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

CDK4 Expression and Activity Are Required for Cytokine Responsiveness in T Cells

Modiano

Mayor

Ball

et al. 2000

The Journal of Immunology

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Stimulation of lymphocytes through the Ag receptor can lead to cytokine responsiveness or unresponsiveness. We examined the importance of cyclin-dependent kinase (CDK)4 to establish and maintain IL-2 responsiveness in human T cells. Our results show that a herbimycin A- and staurosporine-sensitive phase of CDK4 expression and activity preceded the acquisition of IL-2-responsiveness in mitogen-stimulated peripheral blood T cells. Intriguingly, CDK4 expression and activity were demonstrable in purified unstimulated peripheral blood T cells from ∼30% (5/16) of healthy individuals examined for this study. These T cells proliferated in response to IL-2 without additional mitogens, and both the expression and activity of CDK4 and the ability to respond to cytokines were resistant to herbimycin A and staurosporine. The pattern of CDK4 expression and response to IL-2 in this subset of individuals resembled that seen in the human IL-2-dependent Kit-225 T cell line. However, in contrast to normal T cells, Kit-225 cells were rendered unresponsive to IL-2 by stimulation through the Ag receptor. In these cells, PHA, anti-CD3, or PMA induced marked reductions of CDK4 expression and activity that paralleled IL-2 unresponsiveness, and these effects were not reversible by IL-2. Furthermore, IL-2-dependent proliferation could be similarly inhibited in Kit-225 cells by overexpression of the CDK inhibitors p16/Ink4-a or p21/Waf-1a or by overexpression of a kinase-inactive CDK4 mutant. The data indicate that CDK4 expression and activity are necessary to induce and maintain cytokine responsiveness in T cells, suggesting that CDK4 is important to link T cell signaling pathways to the machinery that controls cell cycle progression.

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“…In mammals, execution of D cyclin-dependent kinases is essential for onset of S phase (Baldin et al, 1993;Bates et al, 1994;Hengstschlager et al, 1999;Jinno et al, 1999a). Fibroblasts express D1 and D3 as major D cyclins and Cdk4 and Cdk6 as their kinase partners (Bates et al, 1994;Sherr, 1995).…”

Section: Introductionmentioning

confidence: 99%