Show simple item record

dc.contributor.advisorNagle, Ray B.en_US
dc.contributor.authorvon Bredow, Dorothea Charlotte Minka Erika, 1966-*
dc.creatorvon Bredow, Dorothea Charlotte Minka Erika, 1966-en_US
dc.date.accessioned2013-05-09T11:35:54Z
dc.date.available2013-05-09T11:35:54Z
dc.date.issued1996en_US
dc.identifier.urihttp://hdl.handle.net/10150/290681
dc.description.abstractMatrix metalloproteinases (MMPs) are involved in many normal and pathological processes that require remodeling of the extracellular matrix. In this dissertation, the distribution of MMPs in human prostate tissue was determined. Matrilysin localized to epithelial cells in prostate ducts surrounded by inflammatory cells, and was focally expressed in carcinoma and prostatic intraepithelial neoplasia, but not in normal glands. Gelatinase A was detected in both benign and malignant prostate tissue in similar amounts. MT-MMP1, an activator of progelatinase A, was present in 100% of the carcinomas, in 88% of the cases with PIN lesions, but only in 34% of the normal glands. Matrilysin converted gelatinase/TIMP-complexes and free gelatinase B into polypeptides with gelatinolytic activity. In contrast, matrilysin was unable to proteolytically cleave gelatinase A/TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Active matrilysin did not enhance the autocatalytic conversion of its own proform. Using indirect immunofluorescence microscopy, degradation of the fibronectin fibrils produced fibroblasts by matrilysin was demonstrated. Fibronectin fibrils represent a major component encountered by tumor cells during invasion. Removal of matrilysin resulted in regrowth of the fibrils, suggesting that matrilysin was not cytotoxic. Stable fragments derived from the gelatin-binding, the heparin-binding, and the cell attachment domains, respectively, of fibronectin, were identified. Their isolation may allow further studies on their influence on cell migration, attachment and signal transduction which are expected to be different from the effects of undegraded fibronectin. Effects of matrilysin on integrins were also investigated. Incubation of beta4, but not of alpha6 or beta1, with matrilysin, resulted in complete degradation in vitro. Thereby a specific fragment of 90 kD was generated, which was not observed with calpain or trypsin. Two putative cleavage sites for matrilysin at residues 107 (isoleucine) and 417 (leucine) located within the extracellular domain of the beta4 were identified by sequence comparisons with known substrates. Degradation of beta4 by matrilysin may partly explain the loss of beta4 integrin in prostate carcinoma. Taken together, the data presented here demonstrate effects of matrilysin on a variety of processes important in carcinogenesis.
dc.language.isoen_USen_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.subjectBiology, Cell.en_US
dc.subjectHealth Sciences, Pathology.en_US
dc.subjectHealth Sciences, Oncology.en_US
dc.titleThe function of matrilysin and other matrix metalloproteinases in human prostate carcinomaen_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
thesis.degree.grantorUniversity of Arizonaen_US
thesis.degree.leveldoctoralen_US
dc.identifier.proquest9720640en_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplineCancer Biologyen_US
thesis.degree.namePh.D.en_US
dc.identifier.bibrecord.b34562783en_US
refterms.dateFOA2018-05-26T00:49:21Z
html.description.abstractMatrix metalloproteinases (MMPs) are involved in many normal and pathological processes that require remodeling of the extracellular matrix. In this dissertation, the distribution of MMPs in human prostate tissue was determined. Matrilysin localized to epithelial cells in prostate ducts surrounded by inflammatory cells, and was focally expressed in carcinoma and prostatic intraepithelial neoplasia, but not in normal glands. Gelatinase A was detected in both benign and malignant prostate tissue in similar amounts. MT-MMP1, an activator of progelatinase A, was present in 100% of the carcinomas, in 88% of the cases with PIN lesions, but only in 34% of the normal glands. Matrilysin converted gelatinase/TIMP-complexes and free gelatinase B into polypeptides with gelatinolytic activity. In contrast, matrilysin was unable to proteolytically cleave gelatinase A/TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Active matrilysin did not enhance the autocatalytic conversion of its own proform. Using indirect immunofluorescence microscopy, degradation of the fibronectin fibrils produced fibroblasts by matrilysin was demonstrated. Fibronectin fibrils represent a major component encountered by tumor cells during invasion. Removal of matrilysin resulted in regrowth of the fibrils, suggesting that matrilysin was not cytotoxic. Stable fragments derived from the gelatin-binding, the heparin-binding, and the cell attachment domains, respectively, of fibronectin, were identified. Their isolation may allow further studies on their influence on cell migration, attachment and signal transduction which are expected to be different from the effects of undegraded fibronectin. Effects of matrilysin on integrins were also investigated. Incubation of beta4, but not of alpha6 or beta1, with matrilysin, resulted in complete degradation in vitro. Thereby a specific fragment of 90 kD was generated, which was not observed with calpain or trypsin. Two putative cleavage sites for matrilysin at residues 107 (isoleucine) and 417 (leucine) located within the extracellular domain of the beta4 were identified by sequence comparisons with known substrates. Degradation of beta4 by matrilysin may partly explain the loss of beta4 integrin in prostate carcinoma. Taken together, the data presented here demonstrate effects of matrilysin on a variety of processes important in carcinogenesis.


Files in this item

Thumbnail
Name:
azu_td_9720640_sip1_m.pdf
Size:
3.231Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record