Cyclin D1 genetic heterozygosity regulates colonic epithelial cell differentiation and tumor number in ApcMin mice.
Constitutive beta-catenin/Tcf activity, the primary transforming events in colorectal carcinoma, occurs through induction of the Wnt pathway or APC gene mutations that cause familial adenomatous polyposis. Mice carrying Apc mutations in their germ line (ApcMin) develop intestinal adenomas. Here, the crossing of ApcMin with cyclin D1-/- mice reduced the intestinal tumor number in animals genetically heterozygous or nullizygous for cyclin D1. Decreased tumor number in the duodenum, intestines, and colons of ApcMin/cyclin D1+/- mice correlated with reduced cellular proliferation and increased differentiation. Cyclin D1 deficiency reduced DNA synthesis and induced differentiation of colonic epithelial cells harboring mutant APC but not wild-type APC cells in vivo. In previous studies, the complete loss of cyclin D1 through homozygous genetic deletion conveyed breast tumor resistance. The protection of mice, genetically predisposed to intestinal tumorigenesis, through cyclin D1 heterozygosity suggests that modalities that reduce cyclin D1 abundance could provide chemoprotection.
The Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Research Building Room E501, 3970 Reservoir Rd., N.W., Box 571468, Washington, DC 20057-1468, USA.
James
J
Hulit
Chenguang
C
Wang
Zhiping
Z
Li
Chris
C
Albanese
Mahadev
M
Rao
Dolores
D
Di Vizio
Salimuddin
S
Shah
Stephen W
SW
Byers
Radma
R
Mahmood
Leonard H
LH
Augenlicht
Robert
R
Russell
Richard G
RG
Pestell
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D003106:Colon / Q000033:anatomy & histology* / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000235:genetics* / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000378:metabolism / Q000473:pathology*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D007417:Intestinal Polyps / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1