Advisor(s)

Roger W. Giese

Contributor(s)

Jerry Zhu, David Soybel, Volkmar Weissig, Alexandro Makriyannis

Date of Award

2008

Date Accepted

7-2008

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

Bouvé College of Health Sciences. School of Pharmacy.

Keywords

Pharmaceutical sciences, Embryogenesis BMP4/Xom beta-catenin LEF/TCF Hom-1, Biology, Cell

Subject Categories

Pharmaceutical technology

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

Formation of the body axis is one of the earliest and the most important steps of embryogenesis. BMP4 and Wnt are the two most important signaling pathways governing the body axis formation and cell fate determination. Deregulation of these two pathways is implicated in tumor genesis, birth defect, and regeneration diseases. Xom, a major transcription factor downstream of BMP4, is a very important homeobox protein with dual roles of transcriptional activation and transcription repression. In spite of the critical role of BMP4/Xom signaling in cell fate determination, the molecular mechanism underlying BMP4/Xom signal transduction is not fully understood. The aim of the thesis is to further understand how BMP4 signaling is transduced through Xom, and how Xom protein level is regulated by ubiquitin medicated proteolysis. I also explored the function of Hom-1, a human Xom homolog. From this thesis study, using the Xenopus model, I made three important observations. First, I learned that Xom complexes with LEF/TCFs and activates LEF/TCF medicated transcription. I demonstrated that this functional interaction is essential for axis formation and cell fate determination. As LEF/TCFs are important transcriptional factors medicating Canonical Wnt signaling pathway, my data suggest that LEF/TCFs may function as a point of convergence to mediate the combined signaling of Wnt and BMP4 pathways during early embryogenesis. Second, I determined that Xom proteolysis is regulated by phosphorylation of the critical serine residues of the Xom destruction motif. Third, I observed that human homolog of Xom (Hom-1) exerts growth inhibitory effects on the growth of cancer cells.

Document Type

Dissertation

Rights Holder

Hong Gao


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