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Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors

(2015) ONCOTARGET. 6(17). p.15425-15435
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Abstract
Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks.
Keywords
EXPRESSION, APOPTOSIS, MYCN, INHIBITION, PHOSPHORYLATION, CDK1, TNF-ALPHA, NEUROBLASTOMA-CELLS, CELL-CYCLE, NEGATIVE BREAST-CANCER, cdk1/CCNB1 complex, cyclin-dependent kinases, cell cycle

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Citation

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Chicago
Schwermer, Melanie, Sangkyun Lee, Johannes Koester, Tom Van Maerken, Harald Stephan, Angelika Eggert, Katharina Morik, Johannes H Schulte, and Alexander Schramm. 2015. “Sensitivity to Cdk1-inhibition Is Modulated by P53 Status in Preclinical Models of Embryonal Tumors.” Oncotarget 6 (17): 15425–15435.
APA
Schwermer, M., Lee, S., Koester, J., Van Maerken, T., Stephan, H., Eggert, A., Morik, K., et al. (2015). Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors. ONCOTARGET, 6(17), 15425–15435.
Vancouver
1.
Schwermer M, Lee S, Koester J, Van Maerken T, Stephan H, Eggert A, et al. Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors. ONCOTARGET. 2015;6(17):15425–35.
MLA
Schwermer, Melanie, Sangkyun Lee, Johannes Koester, et al. “Sensitivity to Cdk1-inhibition Is Modulated by P53 Status in Preclinical Models of Embryonal Tumors.” ONCOTARGET 6.17 (2015): 15425–15435. Print.
@article{6972298,
  abstract     = {Dysregulation of the cell cycle and cyclin-dependent kinases (cdks) is a hallmark of cancer cells. Intervention with cdk function is currently evaluated as a therapeutic option in many cancer types including neuroblastoma (NB), a common solid tumor of childhood. Re-analyses of mRNA profiling data from primary NB revealed that high level mRNA expression of both cdk1 and its corresponding cyclin, CCNB1, were significantly associated with worse patient outcome independent of MYCN amplification, a strong indicator of adverse NB prognosis. Cdk1 as well as CCNB1 expression were readily detectable in all embryonal tumor cell lines investigated. Pharmacological inhibition or siRNA-mediated knockdown of cdk1/CCNB1 induced proliferation arrest independent of MYCN status in NB cells. Sensitivity to cdk1 inhibition was modulated by TP53, which was demonstrated using isogenic cells with wild-type TP53 expressing either dominant-negative p53 or a short hairpin RNA directed against TP53. Apoptosis induced by cdk1 inhibition was dependent on caspase activation and was concomitant with upregulation of transcriptional targets of TP53. Our results confirm an essential role for the cdk1/CCNB1 complex in tumor cell survival. As relapsing embryonal tumors often present with p53 pathway alterations, these findings have potential implications for therapy approaches targeting cdks.},
  author       = {Schwermer, Melanie and Lee, Sangkyun and Koester, Johannes and Van Maerken, Tom and Stephan, Harald and Eggert, Angelika and Morik, Katharina and Schulte, Johannes H and Schramm, Alexander},
  issn         = {1949-2553},
  journal      = {ONCOTARGET},
  keyword      = {EXPRESSION,APOPTOSIS,MYCN,INHIBITION,PHOSPHORYLATION,CDK1,TNF-ALPHA,NEUROBLASTOMA-CELLS,CELL-CYCLE,NEGATIVE BREAST-CANCER,cdk1/CCNB1 complex,cyclin-dependent kinases,cell cycle},
  language     = {eng},
  number       = {17},
  pages        = {15425--15435},
  title        = {Sensitivity to cdk1-inhibition is modulated by p53 status in preclinical models of embryonal tumors},
  volume       = {6},
  year         = {2015},
}

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