CD44 is anti-apoptotic in the murine colonic epithelium
By: by Minalini Lakshman.
Published: 2006
Language: eng
Number of pages: 134
ISBN-13: 9780494158395
Description: CD44 is a unique adhesion molecule in that it facilitates both cell-cell and cell-matrix interactions. These adhesive interactions are important in maintaining colonic crypt homeostasis which is characterized by migration of epithelial cells from the crypt base to the luminal surface where cell detachment and apoptosis occurs. Dysregulation of this process is a feature of neoplastic transformation and defective apoptosis is evident in colon carcinogenesis. Although dysregulated expression of CD44 occurs consistently during this transformation, how it contributes to carcinogenesis remains unknown. I, therefore, hypothesized that CD44 plays an anti-apoptotic role in the colonic epithelium, in conjunction with other anti-apoptotic proteins.I used a CD44 knockout murine model to investigate the role of CD44 in apoptosis in the colon, and the factors involved in mediating its anti-apoptotic role. I found that CD44 expression was associated with an anti-apoptotic phenotype in the colonic epithelium, at the ultrastructural and molecular level. Supporting evidence in CD44-/- colon included abnormal mitochondrial ultrastructure and activation of caspase 3. Furthermore, I demonstrated the involvement of the mitochondrial pathway of apoptosis in CD44-/- colon as shown by activation of caspase 9 and an imbalance between pro and anti-apoptotic members of the Bcl-2 family. In addition, comparable Ki-67 expression and BrdU labeling in the crypt epithelium demonstrated that CD44 deficiency did not alter proliferation, which works in concert with apoptosis to maintain colonic epithelium homeostasis. Therefore, I concluded that loss of CD44 rendered the colonic epithelium predisposed to apoptosis. I further investigated into this protective role of CD44 using whole mouse irradiation to induce apoptosis in the colonic epithelium. I found that CD44 deficiency was associated with significant increase in apoptotic bodies and enhanced caspase 3 activation. Susceptibility to radiation induced apoptosis in CD44 deficient cells involved the mitochondrial pathway exclusively based on activation of caspase 9 and not 8. Collectively, my study identified an anti-apoptotic role to CD44 in the colonic epithelium. This role is relevant to the biology of colorectal neoplasia as it provides an understanding of the consequences of overexpression of CD44 in colonic adenomas and carcinomas.
Notes: Source: Dissertation Abstracts International, Volume: 67-06, Section: B, page: 2919.

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

Includes bibliographic references.

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