Requirements for Cell Cycle Arrest by p16INK4a

Bruce, Jacqueline L.; Hurford, Robert; Classon, Marie; Koh, James; Dyson, Nicholas J.

doi:10.1016/s1097-2765(00)00072-1

Cited by 116 publications

(88 citation statements)

References 48 publications

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“…Additionally, our data strongly suggest that the role of Mip/LIN-9 in G 0 /G 1 is exerted only within the context of p107 and Cell cycle-specific interactions of mammalian Mip/LIN-9 M Pilkinton et al p130, and that it is very unlikely that Mip/LIN-9 has a physiologically meaningful interaction with pRB as previously reported by Gagrica et al (2004). Given the specificity of Mip/LIN-9 for the p107,p130/E2F4 repressor complex, it is tempting to speculate that CDK4 regulates pathways that lead to inactivation of the pocket proteins in a nonlinear manner as previously proposed by Bruce et al (2000). In this model (Figure 6), a repressor complex including p107,p130, E2F4 and Mip/LIN-9 responsible for the regulation of the expression of S/M phase genes is disrupted in G 0 /G 1 by CDK4 phosphorylation allowing the switch of Mip/LIN-9 to an association with B-Myb in late G 1 /early S phase that results in the stabilization of this protein (Pilkinton et al, 2007).…”

Section: Discussionmentioning

confidence: 73%

“…Figure 6 Schematic representation of a model postulating the specific regulation of S/M genes by CDK4. As proposed by Bruce et al (2000), the pocket protein pathway is shown as a nonlinear pathway downstream of CDK4. The activation of CDK4 has several consequences: (a) the inactivation of p107,p130 that results in derepression of G 1 /S genes, among them B-Myb; (b) the release of Mip/ LIN-9 from the p107,p130 repressor complex; and (c) the initial phosphorylation of retinoblastoma protein (pRB).…”

Section: Immunoprecipitations and Immunoblottingmentioning

confidence: 99%

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Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

2007

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Mammalian Mip/LIN-9 is a cell cycle regulatory protein that is negatively regulated by CDK4/cyclin D. It has been demonstrated that Mip/LIN-9 collaborates with B-Myb during S and G 2 /M in the induction of cyclins A and B, and CDK1. The ortholog of Mip/LIN-9 in Drosophila, Mip130, is part of a large multisubunit protein complex that includes RBF, repressor E2Fs and Myb, in what was termed the dREAM complex. A similar complex, although lacking B-Myb, was also described in Caenorhabditis elegans. Here, we demonstrate that unlike Drosophila, Mip/LIN-9 has mutually exclusive and cell cycle-phasespecific interactions with the mammalian orthologs of the dREAM complex. In G 0 /early G 1 , Mip/LIN-9 forms a complex with E2F4 and p107 or p130, while in late G 1 /S phase, it associates with B-Myb. The separation of Mip/LIN-9 from p107,p130/E2F4 is likely driven by phosphorylation of the pocket proteins by CDK4 since Mip/LIN-9 fails to interact with phosphorylated forms of p107,p130. Importantly, the repressor complex that Mip/LIN-9 forms with p107 takes functional precedence over the transcriptional activation linked to the Mip/LIN-9 and B-Myb interaction since expression of p107 blocks the activation of the cyclin B promoter triggered by B-Myb and Mip/LIN-9.

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Section: Discussionmentioning

confidence: 73%

Section: Immunoprecipitations and Immunoblottingmentioning

confidence: 99%

Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

2007

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“…3 The activity of pRb is primarily determined by p16INK4a, an inhibitor of cyclin D-dependent kinases. 4 Loss of p16INK4a, as is frequently found in tumor cells, is sufficient to inactivate the Rb pathway. Accordingly, ectopic p16INK4a is a potent inducer of cellular senescence, provided pRb is present.…”

Section: Introductionmentioning

confidence: 99%

Cooperation between p53 and p130(Rb2) in induction of cellular senescence

et al. 2005

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To determine pathways cooperating with p53 in cellular senescence when the retinoblastoma protein (pRb)/p16INK4a pathway is defunct, we stably transfected the p16INK4a-negative C6 rat glioma cell line with a temperature-sensitive mutant p53. Activation of p53 induces a switch in pocket protein expression from pRb and p107 to p130(Rb2) and stalls the cells in late G1, early S-phase at high levels of cyclin E. Maintenance of the arrest depends on the functions of p130(Rb2) repressing cyclin A. Inactivation of p53 in senescent cultures restores the pocket proteins to initial levels and initiates progression into S-phase, but the cells fail to resume proliferation, likely due to DNA damage becoming apparent in the arrest and activating apoptosis subsequent to the release from p53-dependent growth suppression. The data indicate that p53 can cooperate selectively with p130(Rb2) to induce cellular senescence, a pathway that may be relevant when the pRb/p16INK4a pathway is defunct.

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“…However, recent results using p107 À/À /p130 À/À MEFs have demonstrated that in addition to pRB, p16 growthinhibitory activity depends on the presence of either p107 or p130. 10 While p16 induces inhibition of CDK4/6 activity and growth arrest, inhibition of CDK4 activity using a dominantnegative CDK4 mutant does not result in growth arrest. 11 In agreement with these results, it has been shown that p16-mediated disruption of CDK4/6 active complexes results in redistribution of the CDK inhibitors (CKIs) p21 Cip1 and p27 Kip1 (reviewed in Sherr and Roberts 9 ).…”

Section: Introduction P16mentioning

confidence: 99%

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

et al. 2004

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Restitution of lost tumor-suppressor activities may be a promising strategy to target specifically cancer cells. However, the action of ectopically expressed tumor-suppressor genes depends on genetic background of tumoral cells. Ectopic expression of p16 INK4a induces either cell cycle arrest or apoptosis in different pancreatic cancer cell lines. We examined the molecular mechanisms mediating these two different cellular responses to p16 overexpression. Ectopic expression of p16 leads to G1 arrest in NP-9 cells by redistributing p21/p27 CKIs and inhibiting cyclin-dependent kinase CDK2 activity. In contrast, in NP-18 cells cyclin E (CycE)/ CDK2 activity is significantly higher and is not downregulated by p16-mediated redistribution of p21/p27. Moreover, inhibition of CDK4 activity with fascaplysine, which does not affect CycE/ CDK2 activity, reduces pocket protein phosphorylation in both cell lines, but fails to induce growth arrest. Like overexpression of p16, fascaplysine induces apoptosis in NP-18 cells, suggesting that inhibition of D-type cyclin/CDK activity in cells with high levels of CycE/CDK2 activity activates an apoptotic pathway. Inhibition of CycE/CDK2 activity via ectopic expression of p21 in NP-18 cells overexpressing p16 induces growth arrest and prevents p16-mediated apoptosis. Accordingly, silencing of p21 expression by using small interfering RNA switches the fate of p16-expressing NP-9 cells from cell cycle arrest to apoptosis. Our data suggest that, after CDK4/6 inactivation, the fate of pancreatic tumor cells depends on the ability to modulate CDK2 activity.

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Requirements for Cell Cycle Arrest by p16INK4a

Cited by 116 publications

References 48 publications

Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

Mammalian Mip/LIN-9 interacts with either the p107, p130/E2F4 repressor complex or B-Myb in a cell cycle-phase-dependent context distinct from the Drosophila dREAM complex

Cooperation between p53 and p130(Rb2) in induction of cellular senescence

The fate of pancreatic tumor cell lines following p16 overexpression depends on the modulation of CDK2 activity

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