The Tumor Suppressor Actions of the Vitamin D Receptor in Skin
Annual rept. 15 Jul 2012-14 Jul 2013
NORTHERN CALIFORNIA INST FOR RESEARCH AND EDUCATION SAN FRANCISCO
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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 HH pathway was either constitutively activated by deletion of patched or inactivated by deletion of sonic hedgehog SHH. In addition we developed mice in which the wnt -catenin pathway was constitutively activated by deletion of exon 3 of -catenin or inactivated by deletion of exons 2-6 of -catenin. These were then bred with mice with the floxed VDR. Following the initial hair follicle cycle these deletions were achieved using a keratinocyte specific and tamoxifen regulated ERT2 K14 driven cre cre recombinase. At this point only one of these models has received the full 40 wk course of UVB, that of the VDR -catenin knockout, and the results did not show the expected protection. However, the other models are currently under investigation both with short term and longer term UVB exposure, with results expected within the coming year.
- Anatomy and Physiology
- Medicine and Medical Research