Deregulated hedgehog signaling plays a central role in the pathogenesis of basal cell carcinomas (BCCs) arising in skin, and a variety of other human cancers. The majority of BCCs harbor loss of function mutations in PTCH1, encoding a receptor for the hedgehog family of proteins, or gain of function mutations affecting the hedgehog signal transducer SMO. Both of these alterations result in constitutive hedgehog signaling, which may be sufficient for BCC development. We have shown that the transcription factor GH2 is the primary effector of physiologic hedgehog signaling, which is required for growth of hair follicle epithelium. Moreover, we have demonstrated that overexpression of GH2 in mice is sufficient for the development of follicle-derived skin tumors that faithfully mimic human BCCs, implicating Gli2 in pathologic hedgehog signaling associated with tumorigenesis. We plan to use novel, conditional mouse models to gain further insight into hedgehog pathway mediated tumorigenesis in skin and elsewhere, addressing the following specific aims. 1) Identify target cells for hedgehog pathway-driven tumorigenesis in skin.
Aim 2) Explore the involvement of deregulated hedgehog signaling in the pathogenesis of extracutaneous tumors.
Aim 3) Assess the collective function of Gli proteins in hedgehog pathway-mediated tumorigenesis. The results of these studies will further our understanding of hedgehog pathway-associated skin cancers by determining where (progenitor cell population), when (relative to the hair growth cycle), and how (downstream effectors) these tumors develop. These fundamental insights into BCC biology will add considerably to our knowledge of hedgehog pathway-associated cancer development. Moreover, the robust mouse models we are generating will provide an invaluable set of tools for further exploring the roles of hedgehog signaling in normal biology and disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA087837-05A1
Application #
6920124
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Mietz, Judy
Project Start
2000-07-01
Project End
2010-03-31
Budget Start
2005-04-04
Budget End
2006-03-31
Support Year
5
Fiscal Year
2005
Total Cost
$307,105
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Dermatology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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