The Tumor Suppressor Actions of the Vitamin D Receptor in Skin
Final rept. 15 Jul 2012 - 14 Jul 2014
NORTHERN CALIFORNIA INST FOR RESEARCH AND EDUCATION SAN FRANCISCO
Pagination or Media Count:
The epidermis of the mouse lacking the vitamin D receptor VDR is susceptible to chemical and UVB induced tumor formation. In previous studies we determined that the hedgehog HH and wnt -catenin pathways were activated in the skin of VDR null mice. These pathways when activated promote proliferation and inhibit differentiation, suggesting the hypothesis that they underlie the predisposition of VDR null mouse epidermis to tumor formation following chemical or UVB induced mutations. Accordingly we developed mice in which the wnt -catenin pathway was either constitutively activated by deletion of exon 3 of the -catenin gene or inactivated by deletion of exons 2-6 of the -catenin gene and mice in which the HH pathway was inactivated by deletion of the Shh gene. These were then bred with mice with the floxed VDR. At four weeks these deletions were achieved using a keratinocyte specific and tamoxifen regulated ERT2 K14 driven cre cre recombinase. The phenotypes were remarkable with disruption of hair follicles and hair follicle cycling. Survival for a number of these genotypes was limited, precluding completing the 40wk UVB time course for all but the VDR -catenin knockout. This double knockout also developed tumors indicating that deletion of -catenin did not show the expected protection. We have also evaluated the acute response of these mouse models to UVB, but the results are pending.
- Medicine and Medical Research