Skip to main content
Article thumbnail
Location of Repository

Dynamic telomerase gene suppression via network effects of GSK3 inhibition

By A.E. Bilsland, S.F. Hoare, K.H. Stevenson, J.A. Plumb, N. Gomez-Roman, C.J. Cairney, S. Burns, K. Lafferty-Whyte, T. Hammonds and W.N. Keith

Abstract

<b>Background</b>: Telomerase controls telomere homeostasis and cell immortality and is a promising anti-cancer target, but few small molecule telomerase inhibitors have been developed. Reactivated transcription of the catalytic subunit hTERT in cancer cells controls telomerase expression. Better understanding of upstream pathways is critical for effective anti-telomerase therapeutics and may reveal new targets to inhibit hTERT expression.\ud \ud <b>Methodology/Principal Findings</b>: In a focused promoter screen, several GSK3 inhibitors suppressed hTERT reporter activity. GSK3 inhibition using 6-bromoindirubin-3′-oxime suppressed hTERT expression, telomerase activity and telomere length in several cancer cell lines and growth and hTERT expression in ovarian cancer xenografts. Microarray analysis, network modelling and oligonucleotide binding assays suggested that multiple transcription factors were affected. Extensive remodelling involving Sp1, STAT3, c-Myc, NFκB, and p53 occurred at the endogenous hTERT promoter. RNAi screening of the hTERT promoter revealed multiple kinase genes which affect the hTERT promoter, potentially acting through these factors. Prolonged inhibitor treatments caused dynamic expression both of hTERT and of c-Jun, p53, STAT3, AR and c-Myc.\ud \ud <b>Conclusions/Significance</b>: Our results indicate that GSK3 activates hTERT expression in cancer cells and contributes to telomere length homeostasis. GSK3 inhibition is a clinical strategy for several chronic diseases. These results imply that it may also be useful in cancer therapy. However, the complex network effects we show here have implications for either setting

Topics: QH426, QH301
Publisher: Public Library of Science
Year: 2009
OAI identifier: oai:eprints.gla.ac.uk:25903
Provided by: Enlighten

Suggested articles

Citations

  1. (2006). Algorithms for network analysis in systems-ADME/Tox using the MetaCore and MetaDrug platforms. doi
  2. (1997). beta-catenin is a target for the ubiquitin-proteasome pathway. doi
  3. (2005). Constitutive activation of GSK3 down-regulates glycogen synthase abundance and glycogen deposition in rat skeletal muscle cells. doi
  4. (2004). Drug insight: Cancer cell immortality-telomerase as a target for novel cancer gene therapies. doi
  5. (1998). Ectopic expression of wnt-5a in human renal cell carcinoma cells suppresses in vitro growth and telomerase activity. doi
  6. (2007). Glycogen synthase kinase-3 (GSK3): inflammation, diseases, and therapeutics. doi
  7. (2008). Glycogen synthase kinase-3 and cancer: good cop, bad cop? doi
  8. (1998). Glycogen synthase kinase3beta regulates cyclin D1 proteolysis and subcellular localization. doi
  9. (2000). Growth inhibition of human glioma cells by transfection-induced P21 and its effects on telomerase activity.
  10. (2001). GSK3 takes centre stage more than 20 years after its discovery. doi
  11. (2008). How shelterin protects Mammalian telomeres. doi
  12. (2008). Inhibition of GSK3 differentially modulates NF-kappaB, CREB, AP-1 and beta-catenin signaling in hepatocytes, but fails to promote TNF-alpha-induced apoptosis. doi
  13. (2005). Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters.
  14. (1993). New adenosine kinase inhibitors with oral antiinflammatory activity: synthesis and biological evaluation. doi
  15. (2004). Oscillations in transcription factor dynamics: a new way to control gene expression. doi
  16. (2003). Oscillatory expression of Hes1, p53, and NF-kappaB driven by transcriptional time delays. doi
  17. (2004). Pharmacological inhibitors of glycogen synthase kinase 3. doi
  18. (1985). Radiation survival parameters of antineoplastic drug-sensitive and -resistant human ovarian cancer cell lines and their modification by buthionine sulfoximine.
  19. (1994). Selective platelet-derived growth factor receptor kinase blockers reverse sistransformation.
  20. (2003). Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. doi
  21. (2003). Structure and function of the feed-forward loop network motif. doi
  22. (2008). Targeting telomerase: Therapeutic options for cancer treatment. doi
  23. (2008). Telomerase and cancer therapeutics. doi
  24. (2002). Telomerase and telomeres: from basic biology to cancer treatment. doi
  25. (2004). The Cyclindependent kinase inhibitor CYC202 (R-roscovitine) inhibits retinoblastoma protein phosphorylation, causes loss of Cyclin D1, and activates the mitogenactivated protein kinase pathway. doi
  26. (2006). The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways. doi
  27. (2006). The PTEN tumor suppressor inhibits telomerase activity in endometrial cancer cells by decreasing hTERT mRNA levels. doi
  28. (2005). The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin ligase. doi
  29. (2000). Toggles and oscillators: new genetic circuit designs. doi
  30. (1999). Tyrosine kinase activity of purified recombinant cytoplasmic domain of platelet-derived growth factor beta-receptor (beta-PDGFR) and discovery of a novel inhibitor of receptor tyrosine kinases. doi
  31. (2008). Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers. doi

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.