A new pathway for mitogen-dependent Cdk2 regulation uncovered in p27Kip1-deficient cells

Coats, Steve; Whyte, Peter; Fero, Matthew L.; Lacy, Susan E.; Chung, Grace; Randel, Erin; Firpo, Eduardo; Roberts, James M.

doi:10.1016/s0960-9822(99)80086-4

Cited by 113 publications

(97 citation statements)

References 81 publications

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“…This activity is mechanistically similar to that of the 'Cip/Kip' family of Cdk inhibitors (CKIs), including p21 Cip1 , p27 Kip1 , and p57 Kip2 , and functions redundantly to these CKIs in some contexts. In this regard, p130 was required to inhibit Cdk2 and to prevent S phase entry in mitogen-deprived p27 À/À fibroblasts (Coats et al, 1999). Similarly, p107 was needed to inhibit Cdk2 and permit mitotic exit in p21 À/À p27 À/À cells that express a stabilized form of cyclin A (Chibazakura et al, 2004).…”

Section: Pocket Protein Regulation Of the G1-s Transition Independenmentioning

confidence: 99%

Pocket proteins and cell cycle control

2005

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Section: Pocket Protein Regulation Of the G1-s Transition Independenmentioning

confidence: 99%

Pocket proteins and cell cycle control

2005

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“…However, the number of B cells in these mice is normal and so are functions of B cells. In serum starved p27 Kip1 deficient fibroblasts, Cdk2 activity is still inhibited [82]. Additionally, p27 Kip1 deficient oligodendrocyte precursor cells do eventually differentiate, but they go through several more cycles before doing so, as compared to p27 Kip1 wild type cells [83].…”

Section: Cdc25a Phosphatasementioning

confidence: 99%

Regulation of the G1 phase of the mammalian cell cycle

2000

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In any multi-cellular organism, the balance between cell division and cell death maintains a constant cell number. Both cell division cycle and cell death are highly regulated events. Whether the cell will proceed through the cycle or not, depends upon whether the conditions required at the checkpoints during the cycle are fulfilled. In higher eucaryotic cells, such as mammalian cells, signals that arrest the cycle usually act at a G1 checkpoint. Cells that pass this restriction point are committed to complete the cycle. Regulation of the G1 phase of the cell cycle is extremely complex and involves many different families of proteins such as retinoblastoma family, cyclin dependent kinases, cyclins, and cyclin kinase inhibitors.Key words: Cell cycle, cyclin dependent kinase, cyclin, cyclin kinase inhibitor. Retinoblastoma family of proteinsThe retinoblastoma family consists of three members: pRb, p107, and p130, that are all important in the cell cycle regulation. Studies from knockout mice showed that pRb null mutation is embryonically lethal, while p107 or p130 knockout mice have no known * Corresponding author.Tel: (301) 517-0355; Fax: (301) 517-0344; E-mail: scottd@usa.redcross.org Abbreviations used in this paper: pRb,retinoblastoma protein; CDK, cyclin dependent kinase; CKI, cyclin kinase inhibitor; IgM, immunoglobulin M; BCR, B cell receptor; BHFR, dihydrofolate reductase; TGF-β, transforming growyh factorβ.

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“…T he Cip/Kip family of cyclin-dependent kinase inhibitors (cki) 2 consists of three family members: p21 Cip1 , p27 Kip1 , and p57 Kip2 . The inhibitor p57 Kip2 is expressed mainly in heart, skeletal muscle, and brain (1) but there is no evidence that this protein is expressed in T lymphocytes.…”

mentioning

confidence: 99%

p21Cip1 and p27Kip1 Act in Synergy to Alter the Sensitivity of Naive T Cells to TGF-β-Mediated G1 Arrest through Modulation of IL-2 Responsiveness

Wolfraim

Walz

James

et al. 2004

The Journal of Immunology

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Induction of G1 arrest by TGF-β correlates with the regulation of p21Cip1 and p27Kip1, members of the Cip/Kip family of cyclin-dependent kinase inhibitors (cki). However, no definitive evidence exists that these proteins play a causal role in TGF-β1-induced growth arrest in lymphocytes. In this report we show the suppression of cell cycle progression by TGF-β is diminished in T cells from mice deficient for both p21Cip1 and p27Kip1 (double-knockout (DKO)) only when activated under conditions of optimal costimulation. Although there is an IL-2-dependent enhanced proliferation of CD8+ T cells from DKO mice, TGF-β is able to maximally suppress the proliferation of DKO T cells when activated under conditions of low costimulatory strength. We also show that the induction of p15Ink4b in T cells stimulated in the presence of TGF-β is not essential, as TGF-β also efficiently suppressed proliferation of T cells from p15Ink4b−/− mice. Finally, although these cki are dispensable for the suppression of T cell proliferation by TGF-β, we now describe a Smad3-dependent down-regulation of cdk4, suggesting a potential mechanism underlying to resistance of Smad3−/− T cells to the induction of growth arrest by TGF-β. In summary, the growth suppressive effects of TGF-β in naive T cells are a function of the strength of costimulation, and alterations in the expression of cki modify the sensitivity to TGF-β by lowering thresholds for a maximal mitogenic response.

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A new pathway for mitogen-dependent Cdk2 regulation uncovered in p27Kip1-deficient cells

Cited by 113 publications

References 81 publications

Pocket proteins and cell cycle control

Pocket proteins and cell cycle control

Regulation of the G1 phase of the mammalian cell cycle

p21Cip1 and p27Kip1 Act in Synergy to Alter the Sensitivity of Naive T Cells to TGF-β-Mediated G1 Arrest through Modulation of IL-2 Responsiveness

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