The Vanderbilt University
Grant: $269,630 - National Institutes of Health - Sep. 2, 2009
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Award Description: p120-catenin (p120) and ?-catenin are armadillo repeat proteins that directly bind and regulate E-cadherin, a major cell-cell adhesion receptor with tumor- and metastasis-suppressor activity. ?-catenin is also an important component of the Wnt signaling pathway downstream of the tumor suppressor Adenomatous Polyposis Coli (APC). APC mutation is the initiating event in over 90% of human colon cancer. The mechanism is complex but clearly involves constitutive activation of ?-catenin’s role in transcription. In contrast to ?-catenin, p120 has not been physically or functionally linked to APC. In cultured epithelial cells, p120 ablation severely impairs cell-cell adhesion by inducing the rapid internalization and destruction of Ecadherin. The parent RO1 for this supplement was based on our p120 conditional knockout mouse, and was designed to advance these studies in an animal model. A major objective was to determine the effects of selective p120 ablation in the intestine – (1) by itself, and (2) in the context of a physiologically relevant tumor-initiating event – ie. mutation of APC. However, while characterizing adenomas from APCMin/+ and APC1638/+ mutant mice, we discovered that p120 is in fact already downregulated by at least 30% in virtually all adenomas tested. Importantly, we also find p120 to be downregulated in early adenomas from human patients with Familial Adenomatous Polyposis (FAP). As preliminary evidence that reduced p120 levels might contribute to the effects of mutant APC, we reduced p120 levels further in APC1638/+ mutant mice by genetically removing a single p120 allele. Indeed, tumor incidence increases dramatically (10 – 100 fold), providing strong evidence that the APC-p120 interaction is physiologically relevant. For this supplement, we seek funds to clarify the relationships between p120, Kaiso and APC and how they relate to the process of adenoma formation.
Project Description: p120-catenin (p120) and ?-catenin are armadillo repeat proteins that directly bind and regulate E-cadherin, a major cell-cell adhesion receptor with tumor- and metastasis-suppressor activity. ?-catenin is also an important component of the Wnt signaling pathway downstream of the tumor suppressor Adenomatous Polyposis Coli (APC). APC mutation is the initiating event in over 90% of human colon cancer. The mechanism is complex but clearly involves constitutive activation of ?-catenin’s role in transcription. In contrast to ?-catenin, p120 has not been physically or functionally linked to APC. In cultured epithelial cells, p120 ablation severely impairs cell-cell adhesion by inducing the rapid internalization and destruction of Ecadherin. The parent RO1 for this supplement was based on our p120 conditional knockout mouse, and was designed to advance these studies in an animal model. A major objective was to determine the effects of selective p120 ablation in the intestine – (1) by itself, and (2) in the context of a physiologically relevant tumor-initiating event – ie. mutation of APC. However, while characterizing adenomas from APCMin/+ and APC1638/+ mutant mice, we discovered that p120 is in fact already downregulated by at least 30% in virtually all adenomas tested. Importantly, we also find p120 to be downregulated in early adenomas from human patients with Familial Adenomatous Polyposis (FAP). As preliminary evidence that reduced p120 levels might contribute to the effects of mutant APC, we reduced p120 levels further in APC1638/+ mutant mice by genetically removing a single p120 allele. Indeed, tumor incidence increases dramatically (10 – 100 fold), providing strong evidence that the APC-p120 interaction is physiologically relevant. For this supplement, we seek funds to clarify the relationships between p120, Kaiso and APC and how they relate to the process of adenoma formation.
Jobs Summary: The recovery act funds for this award helped to create or retain the type of position such as research fellow. (Total jobs reported: 1)
Project Status: Less Than 50% Completed
This award's data was last updated on Sep. 2, 2009. Help expand these official descriptions using the wiki below.
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