Cdk2 Deficiency Decreases ras/CDK4-Dependent Malignant Progression, but Not myc-Induced Tumorigenesis

Macías, Everardo; Kim, Yongbaek; Marval, Paula L. Miliani de; Klein‐Szanto, Andres J.; Rodriguez‐Puebla, Marcelo L.

doi:10.1158/0008-5472.can-07-2119

Cited by 25 publications

(27 citation statements)

References 48 publications

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“…This is consistent with the observation that malignant transformation of human cells requires hTERT, oncogenic Ras, st expression, and inactivation of the p53 and pRB pathways (51). Considering that activated Ras cooperates with cyclin E in the transformation of rodent fibroblasts (53) and that Ras-CDK4-dependent tumorigenesis in the mouse skin is susceptible to CDK2 ablation (49), it is possible that full malignant transformation by coexpression of cyclin E and st in NHF requires alterations in Ras signaling. In regard to the selectivity between cooperating oncogenes, it is also important to note that st did not cooperate with cyclin D1 to induce mitogenic independent cell cycle entry (Fig.…”

Section: Discussionsupporting

confidence: 87%

“…In fact, CDK2 knockdown or pharmacologic inhibition specifically inhibits human melanoma cell proliferation and colony formation, indicating that CDK2 activity is required in certain human cancers (47), despite being dispensable for proliferation of other human tumor cells (48). Moreover, in mouse Ras-dependent skin tumorigenesis models where CDK4 expression is driven by a tissue specific promoter, ablation of CDK2 results in decreased incidence and multiplicity of skin tumors (49). In contrast, CDK2 ablation does not affect the incidence of c-Myc-induced tumors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Cyclin E and SV40 Small t Antigen Cooperate to Bypass Quiescence and Contribute to Transformation by Activating CDK2 in Human Fibroblasts*

Sotillo

Garriga

Kurimchak

et al. 2008

Journal of Biological Chemistry

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Cyclin E overexpression is observed in multiple human tumors and linked to poor prognosis. We have previously shown that ectopic expression of cyclin E is sufficient to induce mitogen-independent cell cycle entry in a variety of tumor/immortal cell lines. Here we have investigated the rate-limiting step leading to cell cycle entry in quiescent normal human fibroblasts (NHF) ectopically expressing cyclin E. We found that in serumstarved NHF, cyclin E forms inactive complexes with CDK2 and fails to induce DNA synthesis. Coexpression of SV40 small t antigen (st), but not other tested oncogenes, efficiently induces mitogen-independent CDK2 phosphorylation on Thr-160, CDK2 activation, and DNA synthesis. Additionally, in contactinhibited NHF ectopically expressing cyclin E, st induces cell cycle entry, continued proliferation, and foci formation. Coexpression of cyclin E and st also bypasses G 0 /G 1 arrests induced by CDK inhibitors. Although CDK2 is dispensable for G 0 /G 1 cell cycle entry and normal proliferation in mammals, CDK2 activity is an essential rate-limiting step in NHF with deregulated cyclin E expression and altered PP2A activity, which endows primary cells with transformed features. Consequently, CDK2 could be targeted therapeutically in tumors that involve these alterations. These data also suggest that alterations prior to cyclin E deregulation facilitate proliferation of tumor cells by bypassing mitogenic requirements and negative regulation by adjacent cells.Cyclin E expression is finely regulated during the cell cycle, and its expression is dramatically reduced in quiescent cells. As cells enter G 1 from G 0 following mitogenic stimulation, D-type cyclin-CDKs 3 partially inactivate pRB/p130, which activates expression of E2F-dependent genes, including the cyclin E gene. Cyclin E binds and activates CDK2 and phosphorylates several substrates, including members of the pRB family, which further facilitates cyclin E accumulation and CDK2 activation. Cyclin E-CDK2 also phosphorylates replication factors, centrosomal proteins, and NPAT/p220, a transcription factor that controls histone synthesis. Cyclin E is subsequently degraded by the proteasome, a process that is tightly regulated and involves two separate ubiquitin ligases (reviewed in Ref. 1). The activity of the cyclin E-CDK2 complex is positively regulated by CAK, which opens the activating T loop in CDK2 via phosphorylation of threonine 160, and negatively regulated by phosphorylation of threonine 14/tyrosine 15 and binding to CDK inhibitors (CKIs), p21 and p27, of the KIP family (reviewed in Ref.2). Cyclin E is overexpressed in many tumors as a result of gene amplification, disrupted proteolysis, and/or alterations in the pRB/E2F pathway. Cyclin E overexpression has been linked to poor prognosis in breast cancer, non-small cell lung carcinoma, larynx squamous cell carcinoma, and adrenocortical tumors (reviewed in Ref.3). Two main mechanisms for cyclin E-associated tumorigenesis have been considered to date: induction of genomic instability and...

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Cyclin E and SV40 Small t Antigen Cooperate to Bypass Quiescence and Contribute to Transformation by Activating CDK2 in Human Fibroblasts*

Sotillo

Garriga

Kurimchak

et al. 2008

Journal of Biological Chemistry

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“…Of note, high-throughput screens have previously uncovered synthetic lethal interactions between oncogenic KRAS and several CDKs, including CDK1, CDK2 and CDK6 (Barbie et al, 2009). Moreover KRAS -mutant tumors were shown to be more sensitive to CDK inhibition than KRAS-wild-type tumors (Macias et al, 2007; Puyol et al, 2010), which might explain their increased sensitivity to miR-214-5p.…”

Section: Discussionmentioning

confidence: 99%

Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers

et al. 2017

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SUMMARY Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation. By profiling the response of over 120 human cancer cell lines, we derived an expression-based algorithm that can predict the response of primary tumors to cell cycle-targeting miRNAs. Using systemic administration of nanoparticle-formulated miRNAs, we inhibited tumor progression in seven mouse xenograft models, including three treatment-refractory patient-derived tumors, without affecting normal tissues. Our results highlight the utility of using cell cycle-targeting miRNAs for treatment of refractory cancer types.

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“…Indeed, Cdk2 is known to have a critical role in melanoma growth (32), and deregulated expression of cyclin E is observed in many cancers and correlates with poor outcome, for instance, in breast cancer (33). Of course this does not necessarily mean that cyclin E/Cdk2 is essential for all tumors or even for all Myc-driven tumors (34,35), because it is possible that in addition to its role in senescence, other functions of Myc, including its stimulation of apoptosis, are rate-limiting for the development of some tumors. Goga et al (36) recently reported that pharmacological inhibition of Cdk1 enhances Myc-induced apoptosis by targeting the antiapoptotic protein survivin.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation

Hydbring

Bahram

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

175

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The MYC and RAS oncogenes are frequently activated in cancer and, together, are sufficient to transform rodent cells. The basis for this cooperativity remains unclear. We found that although Ras interfered with Myc-induced apoptosis, Myc repressed Ras-induced senescence, together abrogating two main barriers of tumorigenesis. Inhibition of cellular senescence required phosphorylation of Myc at Ser-62 by cyclin E/cyclin-dependent kinase (Cdk) 2. Cdk2 interacted with Myc at promoters, where it affected Myc-dependent regulation of genes, including Bmi-1, p16, p21, and hTERT, which encode proteins known to control senescence. Repression of senescence by Myc was abrogated by the Cdk inhibitor p27Kip1, which is induced by antiproliferative signals like IFN-γ or by pharmacological inhibitors of Cdk2 but not by inhibitors of other Cdks. In contrast, a phospho-mimicking Myc-S62D mutant was resistant to these manipulations. Inhibition of cyclin E/Cdk2 reversed the senescence-associated gene expression pattern imposed by Myc/cyclin E/Cdk2. This indicates a role of Cdk2 as a transcriptional cofactor and activator of the antisenescence function of Myc and provides mechanistic insight into the Myc-p27Kip1 antagonism. Finally, our findings highlight that pharmacological inhibition of Cdk2 activity is a potential therapeutical principle for cancer therapy, in particular for tumors with activated Myc or Ras.oncogenes | transcription | cell cycle | p27Kip1 | cyclin E

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Cdk2 Deficiency Decreases ras/CDK4-Dependent Malignant Progression, but Not myc-Induced Tumorigenesis

Cited by 25 publications

References 48 publications

Cyclin E and SV40 Small t Antigen Cooperate to Bypass Quiescence and Contribute to Transformation by Activating CDK2 in Human Fibroblasts*

Cyclin E and SV40 Small t Antigen Cooperate to Bypass Quiescence and Contribute to Transformation by Activating CDK2 in Human Fibroblasts*

Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers

Phosphorylation by Cdk2 is required for Myc to repress Ras-induced senescence in cotransformation

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