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Calcium Dependency of Human Matrix Metalloproteinase-26 and Its Potential Contribution to Early-Stage Adenocarcinoma

Title: Calcium Dependency of Human Matrix Metalloproteinase-26 and Its Potential Contribution to Early-Stage Adenocarcinoma.
Name(s): Lee, Seakwoo, 1970-, author
Sang, Qing-Xiang Amy, professor directing dissertation
Keller, Laura R., outside committee member
Li, Hong, committee member
Hilinski, Edwin F., committee member
Department of Chemistry and Biochemistry, degree granting department
Florida State University, degree granting institution
Type of Resource: text
Genre: Text
Issuance: monographic
Date Issued: 2007
Publisher: Florida State University
Florida State University
Place of Publication: Tallahassee, Florida
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Human matrix metalloproteinases-26 (MMP-26/endometase/matrilysin-2) is a newly identified MMP. MMP-26 has one high- and low-affinity calcium binding sites, C1 and C3, respectively, and loss of low-affinity Ca2+ induces tertiary structural changes resulting in dramatic decrease of enzymatic function without secondary structural change. Subsequent loss of high-affinity Ca2+ results in irreversible enzymatic deactivation without further tertiary and secondary structure change. No secondary structural change is associated with the loss of high- or low-affinity Ca2+. Calcium titration revealed calcium dissociation constant (KD1) value of 63 nM at the high-affinity calcium binding site, and KD2 value of 120 mM at the low-affinity calcium binding site. Mutagenesis studies at the putative low-affinity calcium binding site revealed that a K189E mutation (C3 site) decreased KD2 value, resulting in 28 mM, while a V184D mutation (C2 site) increased KD2 value, resulting in 240 mM. K189E mutant acquires lower Ca2+ for active conformation, whereas V184D mutant acquires higher Ca2+. These lead to the conclusion that structure and function of MMP-26 may be regulated by the calcium concentration. Prostate cancer tissue analyses show the expressions of the MMP-26 and TIMP-4. Co-immunoprecipitation revealed a possible MMP-26/TIMP-4 complex formation. Disruption of the basal cell layer is necessary for high-grade prostatic intraepithelial neoplasia (HGPIN) to proceed toward cancer. Immunohistochemistry analysis of prostate cancer tissue slides shows that the expression levels of MMP-26 and TIMP-4 are highest in HGPIN. Moreover, immunohistochemical staining of serially sectioned prostate cancer tissue slides reveals similar patterns of staining for MMP-26 and TIMP-4 on adjacent sections. Therefore, MMP-26 and TIMP-4 are expressed in the HGPIN simultaneously. The highest levels of MMP-26 and TIMP-4 in HGPIN suggest that they might be biomarkers for the early detection of the prostate cancer.
Identifier: FSU_migr_etd-3190 (IID)
Submitted Note: A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Degree Awarded: Summer Semester, 2007.
Date of Defense: June 28, 2007.
Keywords: Homology Modeling, High-Grade Intraepithelial Neoplasia, Immunohistochemistry, Calcium, MMP-26
Bibliography Note: Includes bibliographical references.
Advisory Committee: Qing-Xiang Amy Sang, Professor Directing Dissertation; Laura R. Keller, Outside Committee Member; Hong Li, Committee Member; Edwin F. Hilinski, Committee Member.
Subject(s): Chemistry
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Host Institution: FSU

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Lee, S. (2007). Calcium Dependency of Human Matrix Metalloproteinase-26 and Its Potential Contribution to Early-Stage Adenocarcinoma. Retrieved from