Ubiquitin-mediated proteolysis plays important roles in governing signaling during early embryogenesis. Dysregulation of proteolysis of early developmental pathways often results in tumor formation in adult life. Exploring proteolysis during early embryogenesis, therefore, offers a unique opportunity to unveil mechanisms pertinent to tumorigenesis. During the investigation covered by my K08 award, we found that Xom, a homeobox transcriptional factor of the BMP4 signaling pathway, was degraded in a stage-specific manner at the onset of gastrulation. We have identified the destruction motif of Xom and the critical potential phosphorylation sites (Ser140 and Ser144) of the destruction motif that are important for Xom stability. We have further shown that the SCF-beta-TRCP is most likely the cellular E3 ubiquitin ligase involved in Xom degradation. Expression of non-degradable Xom disrupts dorsoventral pattern formation during early Xenopus embryogenesis, indicating the importance of regulated proteolysis during early embryogenesis. Two important questions remains: 1) how is Xom stabilized during pre-gastrulation phase and 2) what turns on Xom proteolysis at the onset of gastrulation. Based on our preliminary studies, we hypothesized that phosphorylation of the Xom destruction motif plays a regulatory role in determining Xom stability during early development, and a serine/threonine kinase phosphorylates Xom at the onset of gastrulation and triggers Xom degradation. We propose to address the following specific aims to test this hypothesis: 1) Define the function of (Ser140/144) phosphorylation in Xom degradation in vitro; 2) Determine a potential regulatory role of (Ser140/144) phosphorylation in Xom degradation in vivo; 3) Identify the kinase that phosphorylates Ser140/144 of Xom during early embryogenesis. Answers to these questions will present the evidence of how stability of homeobox function is regulated developmentally, which will bear great implications for understanding not only the basic mechanism of embryogenesis but also a broad spectrum of diseases, such as pathogenesis of neoplasm.
| Gao, Hong; Le, Yi; Wu, Xiaoming et al. (2010) VentX, a novel lymphoid-enhancing factor/T-cell factor-associated transcription repressor, is a putative tumor suppressor. Cancer Res 70:202-11 |
