title: Functional characterization of tissue inhibitor of metalloproteinase-1 (TIMP-1) N- and C-terminal domains during Xenopus laevis development.
abstract: Extracellular matrix (ECM) remodeling is essential for facilitating developmental processes. ECM remodeling, accomplished by matrix metalloproteinases (MMPs), is regulated by endogenous tissue inhibitors of metalloproteinases (TIMPs). While the TIMP N-terminal domain is involved in inhibition of MMP activity, the C-terminal domain exhibits cell-signaling activity, which is TIMP and cell type dependent. We have previously examined the distinct roles of the Xenopus laevis TIMP-2 and -3 C-terminal domains during development and here examined the unique roles of TIMP-1 N- and C-terminal domains in early X. laevis embryos. mRNA microinjection was used to overexpress full-length TIMP-1 or its individual N- or C-terminal domains in embryos. Full-length and C-terminal TIMP-1 resulted in increased lethality compared to N-terminal TIMP-1. Overexpression of C-terminal TIMP-1 resulted in significant decreases in mRNA levels of proteolytic genes including TIMP-2, RECK, MMP-2, and MMP-9, corresponding to decreases in MMP-2 and -9 protein levels, as well as decreased MMP-2 and MMP-9 activities. These trends were not observed with the N-terminus. Our research suggests that the individual domains of TIMP-1 are capable of playing distinct roles in regulating the ECM proteolytic network during development and that the unique functions of these domains are moderated in the endogenous full-length TIMP-1 molecule.
authors.affiliation: Department of Biology, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
authors.forename: M A
authors.initials: MA
authors.lastname: Nieuwesteeg
authors.affiliation: Department of Biology, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
authors.forename: J A
authors.initials: JA
authors.lastname: Willson
authors.affiliation: Department of Biology, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
authors.forename: M
authors.initials: M
authors.lastname: Cepeda
authors.affiliation: Department of Biology, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
authors.forename: M A
authors.initials: MA
authors.lastname: Fox
authors.affiliation: Department of Biology, University of Western Ontario, 1151 Richmond Street, London, ON, Canada N6A 5B7.
authors.forename: S
authors.initials: S
authors.lastname: Damjanovski
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D014982:Xenopus laevis / Q000196:embryology*
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1