Cyclin D1 is not an immediate target of beta-catenin following Apc loss in the intestine.
Cyclin D1 is postulated to be a target of the canonical Wnt pathway and critical for intestinal adenoma development. We show here that, unlike cyclin D1 reporter assays, endogenous cyclin D1 levels are not affected following antagonism of the Wnt pathway in vitro, nor is cyclin D1 immediately up-regulated following conditional loss of Apc in vivo. Cyclin D1 levels do, however, increase in a delayed manner in a small subset of cells, suggesting such up-regulation occurs as a secondary event. We also analyzed the immediate consequences of Apc loss in a cyclin D1(-/-) background and failed to find any cyclin D1-dependent phenotypes. However, we did observe elevated cyclin D1 expression in lesions developing 20 days after Apc loss. In these circumstances, all adenomas (but not smaller lesions) showed cyclin D1 up-regulation. Finally in a smaller study, we analyzed whether cyclin D1 deficiency affected adenoma formation 20 days following induced loss of Apc. Unlike AhCre(+) Apc(fl/fl) mice (which all developed adenomas), doubly mutant AhCre(+) Apc(fl/fl) cyclin D1(-/-) mice only developed small lesions. Taken together, this argues that cyclin D1 up-regulation in intestinal neoplasia is important for tumor progression rather than initiation.
Sansom
Owen J
OJ
School of Biosciences, University of Cardiff, Museum P. O. Box 911, Cardiff CF103US, Wales, United Kingdom. o.sansom@beatson.gla.ac.uk
Reed
Karen R
KR
van de Wetering
Marc
M
Muncan
Vanesa
V
Winton
Douglas J
DJ
Clevers
Hans
H
Clarke
Alan R
AR
D000236:Adenoma; D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms; D019938:Cyclin D1 / Q000235:genetics / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D019426:Integrases / Q000378:metabolism; D007414:Intestinal Neoplasms; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; C045073:Cre recombinase; D019426:Integrases