Home > Research > Publications & Outputs > Mitogenic growth signalling, DNA replication li...

Text available via DOI:

View graph of relations

Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Published

Standard

Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. / Dudderidge, Tim; McCracken, S.R.; Loddo, Marco et al.
In: British Journal of Cancer, Vol. 96, No. 9, 2007, p. 1384-1393.

Research output: Contribution to Journal/MagazineJournal articlepeer-review

Harvard

Dudderidge, T, McCracken, SR, Loddo, M, Fanshawe, T, Kelly, JD, Neal, DE, Leung, HY, Williams, G & Stoeber, K 2007, 'Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer', British Journal of Cancer, vol. 96, no. 9, pp. 1384-1393. https://doi.org/10.1038/sj.bjc.6603718

APA

Dudderidge, T., McCracken, S. R., Loddo, M., Fanshawe, T., Kelly, J. D., Neal, D. E., Leung, H. Y., Williams, G., & Stoeber, K. (2007). Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. British Journal of Cancer, 96(9), 1384-1393. https://doi.org/10.1038/sj.bjc.6603718

Vancouver

Dudderidge T, McCracken SR, Loddo M, Fanshawe T, Kelly JD, Neal DE et al. Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. British Journal of Cancer. 2007;96(9):1384-1393. doi: 10.1038/sj.bjc.6603718

Author

Dudderidge, Tim ; McCracken, S.R. ; Loddo, Marco et al. / Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. In: British Journal of Cancer. 2007 ; Vol. 96, No. 9. pp. 1384-1393.

Bibtex

@article{4cdd53261bac4c3db3cddaa333fc3ffa,
title = "Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer",
abstract = "Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67LI-gemininLI; (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2LI-Ki67LI; (P=0.01)) and accelerated cell cycle progression (gemininLI/Ki67LI; (P= 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication",
author = "Tim Dudderidge and S.R. McCracken and Marco Loddo and Thomas Fanshawe and J.D. Kelly and D.E. Neal and H.Y. Leung and Gareth Williams and Kai Stoeber",
year = "2007",
doi = "10.1038/sj.bjc.6603718",
language = "English",
volume = "96",
pages = "1384--1393",
journal = "British Journal of Cancer",
issn = "1532-1827",
publisher = "Nature Publishing Group",
number = "9",

}

RIS

TY - JOUR

T1 - Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer

AU - Dudderidge, Tim

AU - McCracken, S.R.

AU - Loddo, Marco

AU - Fanshawe, Thomas

AU - Kelly, J.D.

AU - Neal, D.E.

AU - Leung, H.Y.

AU - Williams, Gareth

AU - Stoeber, Kai

PY - 2007

Y1 - 2007

N2 - Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67LI-gemininLI; (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2LI-Ki67LI; (P=0.01)) and accelerated cell cycle progression (gemininLI/Ki67LI; (P= 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication

AB - Activation of mitogen/extracellular-signal-regulated kinase kinase 5/extracellular signal-regulated kinase-5 (MEK5/ERK5) growth signalling is coupled to increased cell proliferation in prostate cancer (PCa). Dysregulation of the DNA replication licensing pathway, a critical step in growth control downstream of transduction signalling pathways, is associated with development of PCa. In this study we have investigated linkages between the MEK5/ERK5 pathway and DNA replication licensing during prostate carcinogenesis. The effects of increased MEK5/ERK5 signalling on the expression of replication licensing factors Mcm2 and geminin and the proliferation marker Ki67 were studied in an ecdysone-inducible system expressing a constitutively activated mutant of MEK5 in EcR293 cells and in stable ERK5 over-expressing PC3 clones. In parallel, expression of these biomarkers in PCa biopsy specimens (n=58) was studied and compared to clinicopathological parameters. In both in vitro systems induction of MEK5 expression resulted in increased levels of phosphorylated ERK5 and Mcm2, geminin and Ki67 proteins. In PCa specimens average Mcm2 expression was greater than Ki67 and geminin expression (median labelling index (LI) 36.7, 18.1, and 3.4% respectively), consistent with their differential expression according to growth status (P<0.0001). Mcm2, geminin and Ki67 expression were significantly associated with Gleason grade (P=0.0002, P=0.0003, P=0.004); however there was no link with T or M stage. There was a significant relationship between increasing ERK5 expression and increasing Mcm2 (P=0.003) and Ki67 (P=0.009) expression, with non-significant trends seen with increasing MEK5 expression. There were significant associations between Gleason grade and the number of cells traversing G1 phase (Ki67LI-gemininLI; (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2LI-Ki67LI; (P=0.01)) and accelerated cell cycle progression (gemininLI/Ki67LI; (P= 0.005)), all indicative of a shift towards increasing proliferative potential. While Mcm2 and Ki67 were both prognostic factors on univariate analysis, only Mcm2 remained an independent prognostic marker on multivariate analysis. Taken together, our data show that induction of MEK5/ERK5 signalling is linked to activation of the DNA replication licensing pathway in PCa, and that the strong prognostic value of MCM proteins may result from their function as relay stations coupling growth regulatory pathways to genome duplication

U2 - 10.1038/sj.bjc.6603718

DO - 10.1038/sj.bjc.6603718

M3 - Journal article

VL - 96

SP - 1384

EP - 1393

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 1532-1827

IS - 9

ER -