Hedgehog signaling, originally described in Drosophila, is one of the most important pathways in vertebrate development. Disruption of this pathway leads to developmental disorders and cancers, particularly basal cell carcinoma. Basal cell carcinoma is the most common form of human cancer, affecting 750,000 Americans per year. UV radiation is the most important risk factor for basal cell carcinomas. Basal cell carcinoma is now understood to be associated with both somatic and germ line gene mutations in the sonic hedgehog signaling pathway. Two genes are commonly mutated, patched or smoothened (SMO). SMO signaling activity is regulated by the sonic hedgehog receptor-patched. However, most of the sonic hedgehog signaling pathway downstream of SMO is unknown or poorly understood. We have shown that the mutant SMO is oncogenic; it can transform cultured cells, and can lead to tumor formation when expressed in mouse skin. Our overall hypothesis is that SMO is the key signal transducer of the pathway, and Gli1 is the ultimate downstream effector for basal cell carcinoma formation. Activation of this pathway leads to increased cell proliferation and tumor formation. Therefore inhibiting the pathway could be effective in slowing tumor formation. In this proposal, we will use the mutant SMO molecule and the downstream molecule Gli1 as biological probes for the identification, isolation and functional dissection of molecular components that collaborate to regulate the hedgehog pathway in basal cell carcinomas. We proposed three specific aims: 1) To determine the significance of PDGFRalpha for basal cell carcinoma formation (Aim 1); 2) To determine how Glil phosphorylation is regulated by PKA and upstream signals (Aim 2); 3) To determine the mechanism of SMO signaling (Aim 3).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA094160-02
Application #
6620624
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Perry, Mary Ellen
Project Start
2002-01-29
Project End
2006-12-31
Budget Start
2003-01-01
Budget End
2003-12-31
Support Year
2
Fiscal Year
2003
Total Cost
$265,220
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771149
City
Galveston
State
TX
Country
United States
Zip Code
77555
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