The Role of the Sonic Hedgehog Pathway for Prostate Cancer Progression
Abstract
The hedgehog pathway plays a critical role in the development of prostate. In the previous funding period, we reported activation of hedgehog signaling in advanced and metastatic tumors. Here we report molecular mechanisms by which activated hedgehog signaling alter cell functions. In one cancer cell line, NCI-H209, we detected promoter methylation of Su(Fu). Ectopic expression of Su(Fu) in NCI-H209 cells down-regulates hedgehog target gene expression and leads to inhibition of BrdU incorporation, a marker for cell proliferation. Thus, inactivation of Su(Fu) is a mechanism by which hedgehog signaling is activated in human cancer. We also investigated the molecular basis by which PKA affects Gli1 activity. We find that activation of PKA retains Gli1 in the cytoplasm. Conversely, inhibition of PKA activity promotes nuclear accumulation of Gli1. Mutation analysis identifies T374 as a major PKA site determining Gli1 protein localization. In the three dimension structure, T374 resides adjacent to the basic-residue cluster of the nuclear localization signal (NLS). Mutation of this residue to Asp (Gli1/T374D) results in more cytoplasmic Gli1 whereas a mutation to Lys (Gli1/T374K) leads to more nuclear Gli1. These data provide evidence to support a model that PKA regulates Gli1 localization, in part, through modulating the NLS function.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2006
- Accession Number
- ADA452305
Entities
People
- Jingwu Xie
Organizations
- University of Texas Medical Branch