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Title: Functional Characterization of Isthmin, A novel secreted protein in Angiogenesis
Authors: XIANG WEI
Keywords: Isthmin, angiognesis, anti-angiogenesis, cancer
Issue Date: 22-Dec-2009
Citation: XIANG WEI (2009-12-22). Functional Characterization of Isthmin, A novel secreted protein in Angiogenesis. ScholarBank@NUS Repository.
Abstract: Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the midbrain-hindbrain organizer in Xenopus with no known functions. It encodes a 60 kDa protein containing a thrombospondin type 1 repeat domain (TSR) in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrated that ISM is a novel angiogenesis inhibitor with functions in physiological as well as pathological angiogenesis. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through interfering with integrin av?5/focal adhesion complex/actin filament assembly pathway downstream of VEGF. It also suppressed VEGF/bFGF-induced in vivo angiogenesis in mouse. In addition, it inhibited various growth factors-stimulated EC proliferation without affecting EC migration and attachment to matrix. Furthermore, ISM induces EC apoptosis in the presence of VEGF through activating caspase 3. Structure-functional analysis suggests that AMOP but not TSR domain mediates the most anti-angiogenic activities of ISM. Overexpression of ISM significantly suppressed mouse B16 melanoma tumor growth through inhibition of tumor angiogenesis without affecting tumor cell proliferation. Knockdown of ism in zebrafish embryos led to disorganized intersegmental vessels in the trunk, indicating that ism is required for embryonic angiogenesis. Our work is the first to demonstrate the inhibitory role of ISM in angiogenesis, which expands the understanding of the complex regulatory mechanisms of angiogenesis and provides a novel potential therapeutic agent for the treatment of cancer.
Appears in Collections:Ph.D Theses (Open)

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