Regulation and Roles of c-Yes in Human Colorectal Cancer

• Main Author: Barraclough, Jane
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2007
• Subjects: Microbiology; Oncology
• ISBN: 0438498097; 9780438498099

Increases in the levels and activity of the non-receptor tyrosine kinases c-Src and c-Yes are often associated with colorectal carcinogenesis. The physiological consequences of increased c-Yes activity during early and late stages of tumorigenesis in addition to the degree of redundancy between c-Yes and c-Src in colorectal cancer cells remain elusive. To study the consequences of increases in c-Yes levels and activity in the later stages of colorectal carcinogenesis, human colorectal cancer cell lines were developed in which c-Yes levels and activity can be inducibly increased by tightly controlled expression of wild type c-Yes or the constitutively active mutants of c-Yes, c-YesY537F and c-Yes?t6aa. C-Yes induction resulted in increased cell motility, but did not promote proliferation either in vitro or in vivo. These results suggest that in later stages of colorectal carcinogenesis, elevations in c-Yes levels and activity may promote cancer spread and metastasis rather than tumour growth. In addition, it was found that the inducible cell lines developed could be used as a platform to test new c-Yes-targeted drugs. A novel difluoro analogue of UCS15A, a reported Src inhibitor that mediates its effects by blocking Src Homology (SH3) domain protein-protein interactions, was biologically evaluated for c-Src or c-Yes specificity, because specificity in protein interactions mediated by the SH3 domains of either c-Src or c-Yes had previously been discovered in fibroblasts. Surprisingly, the novel difluoro analogue appeared to activate c-Src and c-Yes rather than having an inhibitory effect.