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Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer.
Br J Cancer. 2007 May 07; 96(9):1384-93.BJ

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 (Ki67(LI)-geminin(LI); (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2(LI)-Ki67(LI); (P=0.01)) and accelerated cell cycle progression (geminin(LI)/Ki67(LI); (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.

Authors+Show Affiliations

Department of Pathology and Royal Free and University College Medical School, University College London, Rockefeller Building, University Street, London, WC1E 6JJ, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17406359

Citation

Dudderidge, T J., et al. "Mitogenic Growth Signalling, DNA Replication Licensing, and Survival Are Linked in Prostate Cancer." British Journal of Cancer, vol. 96, no. 9, 2007, pp. 1384-93.
Dudderidge TJ, McCracken SR, Loddo M, et al. Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. Br J Cancer. 2007;96(9):1384-93.
Dudderidge, T. J., McCracken, S. R., Loddo, M., Fanshawe, T. R., Kelly, J. D., Neal, D. E., Leung, H. Y., Williams, G. H., & Stoeber, K. (2007). Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. British Journal of Cancer, 96(9), 1384-93.
Dudderidge TJ, et al. Mitogenic Growth Signalling, DNA Replication Licensing, and Survival Are Linked in Prostate Cancer. Br J Cancer. 2007 May 7;96(9):1384-93. PubMed PMID: 17406359.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mitogenic growth signalling, DNA replication licensing, and survival are linked in prostate cancer. AU - Dudderidge,T J, AU - McCracken,S R, AU - Loddo,M, AU - Fanshawe,T R, AU - Kelly,J D, AU - Neal,D E, AU - Leung,H Y, AU - Williams,G H, AU - Stoeber,K, Y1 - 2007/04/03/ PY - 2007/4/5/pubmed PY - 2007/9/13/medline PY - 2007/4/5/entrez SP - 1384 EP - 93 JF - British journal of cancer JO - Br. J. Cancer VL - 96 IS - 9 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 (Ki67(LI)-geminin(LI); (P=0.001)), with high ERK5 levels associated with both an increase in replication licensed but non-cycling cells (Mcm2(LI)-Ki67(LI); (P=0.01)) and accelerated cell cycle progression (geminin(LI)/Ki67(LI); (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. SN - 0007-0920 UR - https://www.unboundmedicine.com/medline/citation/17406359/Mitogenic_growth_signalling_DNA_replication_licensing_and_survival_are_linked_in_prostate_cancer_ L2 - http://dx.doi.org/10.1038/sj.bjc.6603718 DB - PRIME DP - Unbound Medicine ER -