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beta-catenin signaling and regulation of cyclin D1 promoter in NRK-49F cells transformed by down-regulation of the tumor suppressor lysyl oxidase.

Abstract
Lysyl oxidase is the enzyme that is essential for collagen and elastin cross-linking. Previous investigations showed that lysyl oxidase is down-regulated in many human tumors and ras-transformed cells. Recently, we proved that antisense down-regulation of lysyl oxidase in NRK-49F cells induced phenotypic changes and oncogenic transformation, characterized by p21(ras) activation and beta-catenin/cyclin D1 up-regulation. In the present paper, we examined beta-catenin intracellular distribution and its association with E-cadherin. We observed an increased association between E-cadherin and beta-catenin in the lysyl-oxidase down-regulated cells during serum starvation. Moreover, we found that beta-catenin cytoplasmic and nuclear levels were increased, suggesting a failure of its down-regulation by the APC-GSK-3beta system, in particular the GSK-3beta phosphorylation of ser-33/37 and thr-41 of beta-catenin. Finally, we investigated the mechanisms leading to the observed cyclin D1 up-regulation. We showed that in the antisense lysyl oxidase cells the cyclin D1 promoter was activated through the LEF and the ATF/CRE sites in the proximal promoter. While the promoter activation through LEF is compatible with beta-catenin signaling, we investigated the possibility that the CRE-dependent activation might be linked to the down-regulation of lysyl oxidase. In fact, up-regulation of lysyl oxidase in a COS-7 cell model showed a significant diminution of the CREB protein binding to the cyclin D1 promoter, leading to a dramatic inhibition of its activity and a significant down-regulation of cyclin D1 protein level in vivo. Finally, our study describes some major anomalies occurring in lysyl oxidase down-regulated fibroblasts, related to beta-catenin signaling and cyclin D1 expression.
AuthorsMonia Giampuzzi, Roberta Oleggini, Chris Albanese, Richard Pestell, Armando Di Donato
JournalBiochimica et biophysica acta (Biochim Biophys Acta) Vol. 1745 Issue 3 Pg. 370-81 (Sep 30 2005) ISSN: 0006-3002 [Print] Netherlands
PMID15946752 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Cadherins
  • beta Catenin
  • Cyclin D1
  • Protein-Lysine 6-Oxidase
  • CREB-Binding Protein
  • GSK3B protein, human
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, rat
  • Glycogen Synthase Kinase 3
Topics
  • Animals
  • COS Cells
  • CREB-Binding Protein (metabolism)
  • Cadherins (metabolism)
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic (metabolism)
  • Chlorocebus aethiops
  • Cyclin D1 (genetics, metabolism)
  • Electrophoretic Mobility Shift Assay
  • Fibroblasts
  • Gene Expression Regulation, Neoplastic
  • Glycogen Synthase Kinase 3 (metabolism)
  • Glycogen Synthase Kinase 3 beta
  • Phosphorylation
  • Promoter Regions, Genetic (genetics)
  • Protein-Lysine 6-Oxidase (metabolism)
  • Rats
  • Signal Transduction (physiology)
  • beta Catenin (metabolism)

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