AuthorDavis, Tracy Lynn
AdvisorCress, Anne E.
MetadataShow full item record
PublisherThe University of Arizona.
RightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
AbstractThe (140 kD) α6 integrin is an essential gene product in epithelial cell maintenance and remodeling of the stratified epithelium. The prostate gland is an example of a glandular epithelium. In prostate cancer, alterations of integrins are observed. Specifically, a shift from α6β4 to persistent expression of α6β1 integrin occurs. Accompanying the loss of polarized α6β4 is loss of its extracellular ligand, laminin-5. Using immunofluorescence staining human prostate, breast and colon tissues, were examined for β4 integrin and laminin-5 expression. Loss of β4 and laminin-5 was apparent beginning in PIN lesions and was absent in prostate carcinoma, differing from retained expression in breast and colon carcinoma. These data suggested progressive loss of β4 integrin and laminin-5 occurs and that this combined defect is unique to prostate cancer progression. A novel 70 kD (non-reduced) variant of the α6 integrin, called α6p for the latin word parvus (small), was identified on the cell surface of normal epithelial and carcinoma cell lines. The α6p variant paired with either β1 or β4 subunits and retained sequences corresponding to the extracellular 'stalk region' and the cytoplasmic tail of the α6 integrin. The β-propeller domain postulated to mediate ligand binding, was missing from this variant. Protein levels of α6p increased three fold during calcium-induced terminal differentiation in a normal mouse keratinocyte model system. Production of the α6p variant was dependent upon an intact actin cytoskeleton. Cell surface α6p was less responsive to changes in the actin cytoskeleton, relative to that observed for α6 and β1 integrins, suggesting α6p did not participate in the focal contact. Additionally, inhibition of serine/threonine phosphatases decreased α6 integrin protein levels, but not α6p integrin, again suggesting the variant functioned as an inactive subunit for signaling. Finally, α6, but not α6p integrin co-immunoprecipitated with hemidesmosome components: laminin-5 and CD151. Preliminary data demonstrated adhesion to synthetic peptide integrin antagonists resulted in a 65 kD form of the alpha6p variant with no alteration of α6 integrin. Together the presented data were consistent with differential regulation of alpha6 and α6p integrins and suggested the α6p variant functioned as an inactive receptor.
Degree ProgramGraduate College