Proliferation of cancer cells despite CDK2 inhibition

Tetsu, Osamu; McCormick, Frank

doi:10.1016/s1535-6108(03)00053-9

Cited by 459 publications

(421 citation statements)

References 52 publications

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“…These steps are frequently deregulated in malignant cells and are therefore potential targets for cancer intervening drugs (Vermeulen et al, 2003). However, recent findings suggested a high functional redundancy of the G1-S regulatory components, like CDK4 and CDK2 (Berthet et al, 2003;Ortega et al, 2003;Tetsu and McCormick, 2003;Malumbres et al, 2004;Sherr and Roberts, 2004). This new insight raises the need for identification of new regulators of the G1-S transition phase.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclindependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1a was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1a and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.

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Section: Discussionmentioning

confidence: 99%

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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“…First, it has been shown that CDK2 activity is dispensable for the growth of different colon carcinoma cell lines, among other tumor cell lines. 38 After that, targeted disruption of CDK2 gene in mice has shown that CDK2 is also dispensable for embryonic development and cell cycle progression, as knocked out mice were fully viable. 39 Reinforcing this idea, CycE1 and CycE2 double knockout mice are also viable and show no major developmental problems.…”

Section: Discussionmentioning

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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“…44 In the presence of elevated E2F, associated with cancer, inhibition of CDK2 can lead to apoptosis. 45 Given recent findings, 1,[9][10][11][12][13][14][15][16]46 there is no reason to think that CDK2 is universally needed to all normal cells. Likely, certain types of normal cells are CDK2 independent.…”

Section: Cdk2: Clinical Applicationsmentioning

confidence: 99%

“…1 Certain cancer cells are insensitive to both endogenous and pharmacological inhibitors of CDKs. For therapy of such cancers, CDK2 inhibitors can be used too, yet for a different purpose: namely, for protection of normal cells from chemotherapy.…”

Section: Cdk2: Clinical Applicationsmentioning

confidence: 99%

Do cells need CDK2 and...Bcr-Abl?

Blagosklonny

2003

Cell Death Differ

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Proliferation of cancer cells despite CDK2 inhibition

Cited by 459 publications

References 52 publications

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

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

Do cells need CDK2 and...Bcr-Abl?

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