scholarly journals Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

Oncogene ◽  
1999 ◽  
Vol 18 (13) ◽  
pp. 2201-2211 ◽  
Author(s):  
Ingeborg Zehbe ◽  
Andreas Rätsch ◽  
Marianna Alunni-Fabbroni ◽  
Annett Burzlaff ◽  
Evi Bakos ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Kinase Inhibitors ◽  
Low Risk ◽  
Cyclin Dependent Kinase ◽  
Cervical Lesions

scholarly journals The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2396
Author(s):  
Nina Schoenwaelder ◽  
Inken Salewski ◽  
Nadja Engel ◽  
Mareike Krause ◽  
Björn Schneider ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Head And Neck ◽  
Kinase Inhibitors ◽  
In Vivo Studies ◽  
Specific Response ◽  
Cyclin Dependent Kinase ◽  
Systematic Analysis ◽  
Mhc I ◽  
Oncological Treatment

Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi’s should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens.

scholarly journals Identification of a cyclin-cdk2 recognition motif present in substrates and p21-like cyclin-dependent kinase inhibitors.

1996 ◽  
Vol 16 (12) ◽  
pp. 6623-6633 ◽  
Author(s):  
P D Adams ◽  
W R Sellers ◽  
S K Sharma ◽  
A D Wu ◽  
C M Nalin ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Cyclin A ◽  
Cdk Inhibitors ◽  
Cyclin Dependent Kinase ◽  
Binding Motifs ◽  
Recognition Motif ◽  
Binding Inhibition ◽  
In Vivo Growth

Understanding how cyclin-cdk complexes recognize their substrates is a central problem in cell cycle biology. We identified an E2F1-derived eight-residue peptide which blocked the binding of cyclin A and E-cdk2 complexes to E2F1 and p21. Short peptides spanning similar sequences in p107, p130, and p21-like cdk inhibitors likewise bound to cyclin A-cdk2 and cyclin E-cdk2. In addition, these peptides promoted formation of stable cyclin A-cdk2 complexes in vitro but inhibited the phosphorylation of the retinoblastoma protein by cyclin A- but not cyclin B-associated kinases. Mutation of the cyclin-cdk2 binding motifs in p107 and E2F1 likewise prevented their phosphorylation by cyclin A-associated kinases in vitro. The cdk inhibitor p21 was found to contain two functional copies of this recognition motif, as determined by in vitro kinase binding/inhibition assays and in vivo growth suppression assays. Thus, these studies have identified a cyclin A- and E-cdk2 substrate recognition motif. Furthermore, these data suggest that p21-like cdk inhibitors function, at least in part, by blocking the interaction of substrates with cyclin-cdk2 complexes.

scholarly journals Cyclin-dependent Kinases Participate in Death of Neurons Evoked by DNA-damaging Agents

1998 ◽  
Vol 143 (2) ◽  
pp. 457-467 ◽  
Author(s):  
David S. Park ◽  
Erick J. Morris ◽  
Jaya Padmanabhan ◽  
Michael L. Shelanski ◽  
Herbert M. Geller ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Sindbis Virus ◽  
Kinase Inhibitors ◽  
Sympathetic Neurons ◽  
Dominant Negative ◽  
Cyclin Dependent Kinase ◽  
Cyclin Dependent Kinases ◽  
Dna Damaging Agents

Previous reports have indicated that DNA-damaging treatments including certain anticancer therapeutics cause death of postmitotic nerve cells both in vitro and in vivo. Accordingly, it has become important to understand the signaling events that control this process. We recently hypothesized that certain cell cycle molecules may play an important role in neuronal death signaling evoked by DNA damage. Consequently, we examined whether cyclin-dependent kinase inhibitors (CKIs) and dominant-negative (DN) cyclin-dependent kinases (CDK) protect sympathetic and cortical neurons against DNA-damaging conditions. We show that Sindbis virus–induced expression of CKIs p16ink4, p21waf/cip1, and p27kip1, as well as DN-Cdk4 and 6, but not DN-Cdk2 or 3, protect sympathetic neurons against UV irradiation– and AraC-induced death. We also demonstrate that the CKIs p16 and p27 as well as DN-Cdk4 and 6 but not DN-Cdk2 or 3 protect cortical neurons from the DNA damaging agent camptothecin. Finally, in consonance with our hypothesis and these results, cyclin D1–associated kinase activity is rapidly and highly elevated in cortical neurons upon camptothecin treatment. These results suggest that postmitotic neurons may utilize Cdk4 and 6, signals that normally control proliferation, to mediate death signaling resulting from DNA-damaging conditions.

Detection of human papillomavirus types by the polymerase chain reaction and the differentiation between high-risk and low-risk cervical lesions

1992 ◽  
Vol 62 (1) ◽  
pp. 167-171 ◽  
Author(s):  
Marion T. E. Cornelissen ◽  
Tom Bots ◽  
Maarten A. Briët ◽  
Maarten F. Jebbink ◽  
Arie P. H. B. Struyk ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Human Papillomavirus ◽  
High Risk ◽  
Low Risk ◽  
Cervical Lesions ◽  
Chain Reaction ◽  
Polymerase Chain

scholarly journals Negative human papillomavirus testing in normal smears selects a population at low risk for developing high-grade cervical lesions

2004 ◽  
Vol 90 (9) ◽  
pp. 1803-1808 ◽  
Author(s):  
C Clavel ◽  
J Cucherousset ◽  
M Lorenzato ◽  
S Caudroy ◽  
J M Nou ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Low Risk ◽  
High Grade ◽  
Cervical Lesions ◽  
Human Papillomavirus Testing

scholarly journals Genotyping of human papillomavirus in cervical lesions by L1 consensus PCR and the Luminex xMAP system

2006 ◽  
Vol 55 (6) ◽  
pp. 715-720 ◽  
Author(s):  
Han-Liang Jiang ◽  
Hai-Hong Zhu ◽  
Lin-Fu Zhou ◽  
Feng Chen ◽  
Zhi Chen
Keyword(s):  
Cervical Cancer ◽  
Human Papillomavirus ◽  
High Risk ◽  
High Throughput ◽  
Invasive Cervical Cancer ◽  
Low Risk ◽  
Cervical Lesions ◽  
Suspension Array ◽  
Hpv Genotypes ◽  
High Risk Hpv

Infection with human papillomavirus (HPV) is the main cause of cervical cancer, the principal cancer in women in most developing countries. Molecular epidemiologic evidence clearly indicates that certain types of HPV are the principal cause of invasive cervical cancer and cervical intraepithelial neoplasia. Comprehensive, high-throughput typing assays for HPV, however, are not currently available. By combining L1 consensus PCR and multiplex hybridization using a Luminex xMAP system-based suspension array, the authors developed a rapid high-throughput assay, the HPV DNA suspension array (HPV-SA), capable of simultaneously typing 26 HPVs, including 18 high-risk HPV genotypes and eight low-risk HPV genotypes. The performance of the HPV-SA applied to 26 synthetic oligonucleotide targets was evaluated. The HPV-SA system perfectly discriminated 18 high-risk HPV targets from eight low-risk HPV targets. To assess the clinical applicability of the assay, the HPV-SA was performed with 133 MY09/MY11 primer set-mediated PCR (MY-PCR)-positive clinical specimens; of the 133 samples, 121 were positive by HPV-SA. Both single and multiple types were easily identified. The authors believe that improvement of the assay may be useful for epidemiological studies, cancer-screening programmes, the monitoring of therapeutic interventions, and the evaluation of the efficacy of HPV vaccine trials.

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