Bcr is a negative regulator of the Wnt signalling pathway.
The Wnt signalling pathway can activate transcription of genes such as c-myc through beta-catenin. Here, we describe the protein breakpoint cluster region, Bcr, as a negative regulator of this pathway. Bcr can form a complex with beta-catenin and negatively regulate expression of c-Myc. Knockdown of Bcr by short interfering RNA relieves the block and activates expression of c-Myc. Expression of Bcr in the human colon carcinoma cell line HCT116, which has a high level of endogenous beta-catenin, leads to reduced c-Myc expression. The negative effect is exerted by the amino terminus of Bcr, which does not harbour the kinase domain. Bcr-Abl, the oncogene protein expressed in chronic myelogenous leukaemia (CML), does not bind to beta-catenin. It phosphorylates Bcr in the first exon sequence on tyrosines, which abrogates the binding of Bcr to beta-catenin. The inhibitor of the Bcr-Abl tyrosine kinase, STI-571 or Gleevec, a drug against CML, reverses this effect. Our data contribute to the understanding of Bcr as a tumour suppressor in the Wnt signalling pathway, as well as in CML.
Ress
Angelika
A
Institute of Medical Virology, University of Zurich, Gloriastrasse 30, 8006 Zurich, Switzerland.
Moelling
Karin
K
D001549:Benzamides; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D005786:Gene Expression Regulation; D016259:Genes, myc / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051562:Proto-Oncogene Proteins c-bcr / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D025521:Tumor Suppressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C496613:BCR protein, human; D051562:Proto-Oncogene Proteins c-bcr