Alterations of the α6β4 and α6β1 integrins in prostate carcinoma

Persistent Link:
http://hdl.handle.net/10150/290157
Title:
Alterations of the α6β4 and α6β1 integrins in prostate carcinoma
Author:
Davis, Tracy Lynn
Issue Date:
2001
Publisher:
The University of Arizona.
Rights:
Copyright © 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.
Abstract:
The (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.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Biology, Cell.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Cancer Biology
Degree Grantor:
University of Arizona
Advisor:
Cress, Anne E.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleAlterations of the α6β4 and α6β1 integrins in prostate carcinomaen_US
dc.creatorDavis, Tracy Lynnen_US
dc.contributor.authorDavis, Tracy Lynnen_US
dc.date.issued2001en_US
dc.publisherThe University of Arizona.en_US
dc.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.en_US
dc.description.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.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectBiology, Cell.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorCress, Anne E.en_US
dc.identifier.proquest3016472en_US
dc.identifier.bibrecord.b41907310en_US
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