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Fox Chase discovery may help physicians diagnose, treat devastating childhood disease

ld explain some cases of the disease not accounted for by previously known genetic changes."

Furthermore, the regulatory sequences discovered in Shin's studies depend on another Hirschsprung-susceptible gene, SOX10, and provide an explanation as to why mutations in SOX10 cause Hirschsprung disease.

Shin was drawn to study Hirschsprung disease because his laboratory has focused on understanding the underlying mechanism mediated by EDNRB. To better understand how defects in this signaling pathway lead to human diseases, Shin's lab has used mouse models to study the early embryonic stages in which these genes are required to form the complex neuronal network needed by the intestine.

"The enhancer sequence we have discovered is important for regulating the EDNRB gene," said Shin. "This sequence is highly conserved between mice and humans. Learning how EDNRB gene expression is normally regulated may help clarify how it is misregulated in cancer and help in designing therapies against these diseases."

In addition to Hirschsprung disease, some patients with mutations at EDNRB have associated syndromes, such as abnormal pigmentation, with white spots in the skin and hair, and hearing loss. Defects in the EDNRB signaling pathway also play a part in other major diseases, including cancer, hypertension and cardiovascular disorders.

Research elsewhere has shown that inappropriate expression of EDNRB can promote cell proliferation and metastasis of tumors, including melanomas and breast and prostate cancer cells. Shin's laboratory has studies in progress to locate the enhancer specific to the EDNRB pathway in pigment-producing cells (melanocytes), from which the serious skin cancer melanoma arises.

Shin's co-authors on the new paper include scientific technician Lei Zhu, M.S., and postdoctoral associate Hyung-Ok Lee, Ph.D., of Fox Chase; former student assistant ChaRandle S. Jordan, now at Stanford University School of Medicine; and V. Ashley C
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Contact: Karen C. Mallet
k_carter@fccc.edu
215-728-2700
Fox Chase Cancer Center
30-May-2004


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