Molecular Basis of Hedgehog Signaling in Carcinogenesis

Project: Research project

Description

DESCRIPTION: (PROVIDED BY APPLICANT) 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).
StatusFinished
Effective start/end date1/29/027/31/13

Funding

  • National Institutes of Health: $258,987.00
  • National Institutes of Health: $273,008.00
  • National Institutes of Health: $75,500.00
  • National Institutes of Health: $287,688.00
  • National Institutes of Health: $267,690.00
  • National Institutes of Health: $267,690.00
  • National Institutes of Health: $265,220.00
  • National Institutes of Health: $265,220.00
  • National Institutes of Health: $273,008.00
  • National Institutes of Health: $265,220.00
  • National Institutes of Health: $264,818.00

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Hedgehogs
Carcinogenesis
Basal Cell Carcinoma
Neoplasms
Basal Cell Neoplasms
Environmental Carcinogens
Transducers
Drosophila
Vertebrates
Platelet-Derived Growth Factor alpha Receptor
Signal Transduction
Germ-Line Mutation
Genes

ASJC

  • Medicine(all)