CK2 as a positive regulator of Wnt signalling and tumourigenesis.
CK2 is upregulated in rapidly dividing cells including most human tumours. Transgenic overexpression of CK2 in lymphoid or mammary lineages predisposes to transformation. Multiple signalling and oncogene pathways could be regulated by CK2 in this process. Our studies suggest that phosphorylation of critical oncogenes by CK2, as well as by other serine-threonine kinases, regulates their stability via susceptibility to the proteasomal degradation system. Beta-catenin is a transcriptional co-factor in the Wnt signalling pathway that is regulated in this fashion. Inactivating mutations in the adenomatosis polyposis coli (APC) gene, which encodes a carrier protein for beta-catenin, or stabilizing mutations in beta-catenin itself, frequently occur in human tumours. CK2 and the monomeric serine-threonine kinase GSK3 have opposing actions on beta-catenin: GSK-3 phosphorylation of the N-terminus of beta-catenin promotes degradation; while phosphorylation by CK2 in the armadillo repeat protein interaction domain protects it. Beta-catenin is overexpressed in mammary tumours occurring in mice transgenic for CK2 or a dominant negative form of GSK3, and also in mammary tumours arising following treatment with the environmental carcinogen DMBA. Experiments are underway to determine whether expression of both CK2 and kinase inactive GSK3 further accelerates tumorigenesis. Inhibitors of GSK3 under development for treatment of diabetes could promote tumours, while CK2 inhibitors should be useful agents for treatment of cancer.
Seldin
David C
DC
Section of Hematology-Oncology, Department of Medicine, Boston University Medical Center, Boston, MA, USA. dseldin@bumc.bu.edu
Landesman-Bollag
Esther
E
Farago
Marganit
M
Currier
Nicolas
N
Lou
David
D
Dominguez
Isabel
I
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D047390:Casein Kinase II / Q000235:genetics / Q000502:physiology*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051153:Wnt Proteins; D051176:beta Catenin; D047390:Casein Kinase II; D038362:Glycogen Synthase Kinase 3