Developmental pathways are networks of genes which act coordinately to establish the body plan. Disruptions of these genes, which can be associated with environmental exposures, can result in serious dysmorphogenesis or cancer in both children and adults. An important goal of environmental science ought to be reduction of these poor outcomes. This will require an understanding of the genes affected by specific exposures and the consequence of alterations in these genes or their products which in turn will require a complete biochemical understanding of the pathways critical in development. The ligand Sonic hedgehog, the receptors Patched and Smoothened, and the GLI family of transcription factors represent one such pathway critical to the normal development of many organs due to their regulation functions at the nexus of mesenchymal differentiation. Environmental exposure to jervine or UVA and UCB disrupts the pathway. Although some gene targets of the pathway are not known from work in Drosophila key downstream targets and upstream regulators remain to be elucidated in mammals and the roles of these molecules established in normal development in order to better understand their role in dysmorphogenesis and neoplasia. For example, basal cell carcinoma (BCC) is the most common cancer in man and mutations in Patched or over-expression of GLI are both strongly associated with BCC. Prostatic cancer is a serious problem in the US and our preliminary evidence suggests an association of GLI expression with prostatic cancer in humans. We have established a unique team of co- investigators of GLI expression with pro-static cancer in humans. We have established a unique team of co-investigators at Northwestern University who study the regulation and function of the homologues of the GLI genes in C. elegans, Drosophila, mouse, and human. We have previously worked together to collaborate on studies of these genes and these efforts will be greatly enhanced by the current program project allowing use of data from Drosophila and C. elegans in the design of experiments in mouse, or with human material. We are uniquely suited to establish the regulation of the GLI genes at a transcriptional, post- transcriptional, and functional (protein-protein interactions) level. The long term goals of our work will be to determine pathways of development involving GLI genes and their interactions with environmental exposure, in order to establish mechanisms of interact with downstream targets. These experiments will provide data of great significance to both normal development, birth defects, and cancer. The work will very likely provide important general models of transcription factor activity whose utility will extend to a wide variety of developmental, birth defects, and cancer. The work will very likely provide important general models of transcription factor activity whose utility will extend to a wide variety of developmental and cancer problems. Clearly understanding the pathways and the biochemical mechanism of action of developmental genes will be necessary in order to determine the role of environmental exposures on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES010549-02
Application #
6382373
Study Section
Special Emphasis Panel (ZES1-JPM-B (PI))
Program Officer
Packenham, Joan P
Project Start
2000-09-30
Project End
2005-07-31
Budget Start
2001-09-30
Budget End
2002-07-31
Support Year
2
Fiscal Year
2001
Total Cost
$582,682
Indirect Cost
Name
Children's Memorial Hospital (Chicago)
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60611
Yoon, Joon Won; Lamm, Marilyn; Iannaccone, Stephen et al. (2015) p53 modulates the activity of the GLI1 oncogene through interactions with the shared coactivator TAF9. DNA Repair (Amst) 34:9-17
Galat, Vasiliy; Zhou, Yue; Taborn, Greg et al. (2007) Overcoming MIII arrest from spontaneous activation in cultured rat oocytes. Cloning Stem Cells 9:303-14
Croker, Jennifer A; Ziegenhorn, Suzanne L; Holmgren, Robert A (2006) Regulation of the Drosophila transcription factor, Cubitus interruptus, by two conserved domains. Dev Biol 291:368-81
Lakiza, Olga; Frater, Leah; Yoo, Young et al. (2005) STAR proteins quaking-6 and GLD-1 regulate translation of the homologues GLI1 and tra-1 through a conserved RNA 3'UTR-based mechanism. Dev Biol 287:98-110
Walterhouse, David O; Lamm, Marilyn L G; Villavicencio, Elisabeth et al. (2003) Emerging roles for hedgehog-patched-Gli signal transduction in reproduction. Biol Reprod 69:8-14
Zhou, Yue; Galat, Vasiliy; Garton, Ray et al. (2003) Two-phase chemically defined culture system for preimplantation rat embryos. Genesis 36:129-33
Lamm, Marilyn L; Catbagan, Winnie S; Laciak, Robert J et al. (2002) Sonic hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev Biol 249:349-66
Villavicencio, Elisabeth H; Yoon, Joon Won; Frank, Daniel J et al. (2002) Cooperative E-box regulation of human GLI1 by TWIST and USF. Genesis 32:247-58
Yoon, Joon Won; Kita, Yasuhiro; Frank, Daniel J et al. (2002) Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 277:5548-55
Kroft, T L; Patterson, J; Won Yoon, J et al. (2001) GLI1 localization in the germinal epithelial cells alternates between cytoplasm and nucleus: upregulation in transgenic mice blocks spermatogenesis in pachytene. Biol Reprod 65:1663-71

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