Novel genes in the pathogenesis of aggressive fibromatosis
By: by Fen Li.
Published: 2006
Language: eng
Number of pages: 224
ISBN-13: 9780494158791
Description: We have discovered mutations in the adenomatous polyposis coli (APC) gene or beta-catenin in the mesenchymal neoplasm, aggressive fibromatosis (AF), and demonstrated beta-catenin mediated TCF-dependent transcriptional activation in this tumor. To study how this mechanism causes AF, I investigated the differentially expressed genes in AF. My hypothesis is that differentially expressed genes in AF are involved in the neoplastic development of AT. In order to identify genes that may be involved in this process, suppression subtractive hybridization was used to compare gene expression differences between cells derived from an AF tumor with an APC mutation to the same cells after transfection with wild-type APC. Plasminogen activator inhibitor-1 (PAI-1) and a novel gene, DRIF-1 (d&barbelow;own-r&barbelow;egulated i&barbelow;n f&barbelow;ibromatosis-1), were found to be differentially expressed in AF. PAI-1 expression was higher in AF tumors compared to the control tissues. PAI-1 deficiency reduced the number of AF tumors formed in a mouse model of AF, and was associated with a decrease in cell proliferation and motility. The full-length of the DRIF-1 gene has been sequenced, and its putative protein structure contains a sterile alpha motif (SAM) domain at its amino terminus. DRIF-1 is located on the human chromosome 7q21.2 with a 5' upstream adjacent predicted paralogous gene (DRIF-2) in the head-to-tail orientation. DRIF-1 was ubiquitously expressed in human tissues. However, its expression was lower in AF tumors and some cases of breast and colon cancers, when compared to normal control tissues from the same patients. The putative protein of DRIF-1 locates to the cytoplasm of living cells. The expression of DRIF-1 in SW480 cells reduced, while deficiency of DRIF-1 in SW480 cells increased the tumor volume formed in immune deficient mice. In vitro data suggests roles for DRIF-1 in cell proliferation, invasion and apoptosis. The role of PAI-1 in the pathogenesis of AF discovered in this thesis supports my hypothesis and suggests a new therapy for AF. The gene structure and potential functions of DRIF-1 investigated in this thesis provide the foundation for further research on this novel gene.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3594.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.