Ann & Robert H. Lurie Children's Hospital of Chicago Box 204
225 E Chicago Avenue
Chicago IL 60611
Description of Interests
The Sonic hedgehog signal in vertebrates is mediated by three C2H2 zinc finger transcription factors, GLI1, GLI2, and GLI3. We have shown that near identity of gene sequence exists between mouse and human GLI1 and that GLI1 functions as a transcription factor and that a critical domain in the COOH end of the protein is a transactivator with VP16-like structure. We established that GLI1 protein regulates a set of genes that coordinately control proliferation and may in part explain malignant transformation by misexpression of GLI1. We have established non-canonical activation of GLI1 by c-myc short-circuiting patched and smoothened trans-membrane proteins in lymphoma. We established that GLI1 binds TAF9 at the gene target and competes with P53 for this adapter protein providing an explanation for GLI1 oncogenic activity. We are working out the mechanisms of autoregulation of GLI1 by molecular analysis of cis and trans effectors using gene editing techniques. We have established a strong intronic enhancer region that in part explains GLI autoregulation. We are establishing key protein-protein interactions during assembly of the transcription machinery. We have developed chimeras and a method to identify cell lineage in visceral organs. We established that chemically induced tumors and preneoplastic lesions are clonal, the first lab to do this. The patterns in normal tissue derive from the allocation of stem cells during development. We show that the patterns are fractal, likely arise from iterating simple division rules and do not require cell movement for complex, highly variegated patterns to form. In the cornea epithelial cells are assorted in spirals. Absence of the pattern is associated with Pax6 mutations and keratopathies. Using finite element models we have shown the patterns correlate with path lines of maximum stress/strain, suggesting that shearing forces are responsible for the pattern.
Cancer Biology; Cell Biology; Cell Imaging; Embryology; Gene Regulation; Stem Cells
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