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The Ron Receptor Tyrosine Kinase in Tissue Morphogenesis

Meyer, Sara
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1258666269

Abstract Details

2009, PhD, University of Cincinnati, Medicine : Cell and Molecular Biology.
The Ron receptor tyrosine kinase is overexpressed in many human cancers including colorectal and breast, and studies have established Ron as a predictor of disease outcome and as a therapeutic target. Ron overexpression and constitutive activation contributes to the tumorigenic properties of human colon cancer cells. Moreover, metastatic dissemination of colon cancer cells from primary orthotopic tumors in mice can be reduced upon Ron knockdown. The majority of hereditary and sporadic colorectal cancers harbor aberrant Apc/β-catenin signaling, however, the relationship between Ron, Apc, and β-catenin signaling in intestinal tumorigenesis is not well understood. We sought to test the requirement of Ron tyrosine kinase signaling for initiation of intestinal tumors in vivo using a well-characterized mouse model of mutant Apc-driven intestinal tumorigenesis. By generating (ApcMin/+ mice with a targeted deletion of the tyrosine kinase domain of Ron (RonTK-/-), we found that Ron is not required for intestinal adenoma formation, and that Ron loss increases tumor burden in a large fraction of mice. Unexpectedly, the loss of Ron in non-transformed intestinal epithelium significantly increases crypt cell proliferation, which may lead to an increased susceptibility to tumor initiation in this model. β-catenin localization and target gene expression were not significantly altered in ApcMin/+;RonTK-/- mouse tumors or normal intestine compared to controls, suggesting that Ron is not required for β-catenin signaling in this model. Like in colon cancer, Ron overexpression has also been observed in approximately half of human breast cancers. Mammary-specific overexpression of Ron in mice results in mammary carcinomas in 100% of mice that metastasize to the lungs and liver, supporting the conclusion that Ron overexpression is a causal oncogenic factor in breast cancer. Interestingly, mammary glands from virgin mice with aberrant Ron expression have dilated mammary ducts and sparse ductal branches. Based on these observations, and that molecules deregulated in breast cancers often have important roles in development, we hypothesized that Ron is a novel regulator of mammary gland morphogenesis. To study Ron in mammary development, RonTK-/- mice were utilized. We found that Ron tyrosine kinase domain-deficient mice had enhanced ductal morphogenesis during puberty, which was also evident when the mice were ovariectomized. Increased ductal elongation and earlier regression of terminal end buds was also observed in RonTK-/- mammary glands. Interestingly, accelerated pubertal mammary development was accompanied by increased phosphorylated MAPK, which was necessary for enhanced RonTK-/- epithelial branching morphogenesis in vitro. Together, these studies identified novel roles for Ron tyrosine kinase in the regulation of normal intestinal tissue homeostasis and normal mammary gland development. Interestingly, these studies identified important new roles for the Ron receptor in normal tissues. These studies not only further our knowledge of Ron receptor biology, but also provide meaningful insight into the potential consequences of Ron loss that might result from a cancer therapy directed at this receptor.
Susan Waltz, PhD (Committee Chair)
Kathleen Goss, PhD (Committee Member)
Christopher Wylie, PhD (Committee Member)
Nelson Horseman, PhD (Committee Member)
Erik Knudsen, PhD (Committee Member)
Sohaib Khan, PhD (Committee Member)
215 p.
Cellular Biology
colon cancer; mammary gland; development; receptor tyrosine kinase; morphogenesis

Recommended Citations

Citations

  • Meyer, S. (2009). The Ron Receptor Tyrosine Kinase in Tissue Morphogenesis [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1258666269

    APA Style (7th edition)

  • Meyer, Sara. The Ron Receptor Tyrosine Kinase in Tissue Morphogenesis. 2009. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1258666269.

    MLA Style (8th edition)

  • Meyer, Sara. "The Ron Receptor Tyrosine Kinase in Tissue Morphogenesis." Doctoral dissertation, University of Cincinnati, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1258666269

    Chicago Manual of Style (17th edition)

ucin1258666269
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© 2009, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.