The Sonic hedgehog-Patched-Gli pathway is a highly conserved signal transduction pathway. Remarkable similarity in gene sequence and function exists from the round worm (C. elegans) to human. A very significant human disease burden is associated with disruption of the pathway and a number of environmental agents (including alcohol, phytoalkloids, bacterial metabolites and sunlight) are known or suspected to disrupt gene function in the pathway. The Sonic hedgehog signal in vertebrates is mediated by three C2H2 zinc finger transcription factors, GLI1, GLI2 and GLI3. Near identity of gene sequence exists between mouse and human GLI1. We established that GLI1 protein regulates a set of genes that coordinately control proliferation and may in part explain malignant transformation by mis-expression of GLI1. Our research is on the regulation of GLI promoters and microarray studies to identify gene targets that involve transformation and oncogenesis particularly of rhabdomyosarcoma and medulloblastoma. The work is collaborative with Dave Walterhouse . We have published the conservation of the human promoter action in patterning in mouse, translational repression of GLI1 through a highly conserved 3' UTR mechanism and mechanisms of regulation of promoter/5'UTR activity by Twist action on tandem E-box motifs.
Expression of reporters in ventral floor plate under the control of the human GLI1 promoter and 5' UTR
Our lab investigates the targets of GLI1 which can both activate and repress genes when it binds gene promoter/enhancer sequences. A set of target genes that GLI1 regulates are involved in maligant transformation. We are currently working on expanded microarray data to identify gene targets of GLI1 important in medulloblastoma a very common and devastating childhood brain tumor.
GLI1 (red)in cancer cells. Tubulin (green) DAPI (blue) show co-localization of GLI1 and tubulin in mitotic spindles (yellow). Image by Dr.. John Patterson.