Please use this identifier to cite or link to this item: http://scholarbank.nus.edu.sg/handle/10635/43523
Title: CHARACTERIZATION OF ADAMTS4 IN CANCER AND ANGIOGENESIS
Authors: NITHYA RAO VELLIYUIR NOTT
Keywords: ADAMTS4, tumorigenesis, angiogenesis, metalloproteinase, TSR, metastasis
Issue Date: 24-Jan-2013
Source: NITHYA RAO VELLIYUIR NOTT (2013-01-24). CHARACTERIZATION OF ADAMTS4 IN CANCER AND ANGIOGENESIS. ScholarBank@NUS Repository.
Abstract: A disintegrin-like and Metalloproteinase with ThromboSpondin motifs-4 (ADAMTS4)/aggrecanase-1 is highly expressed in cartilage and has been implicated in human arthritis. Although abundantly expressed in many types of cancer, its role in cancer remains unknown. In this study, we report for the first time a novel function for ADAMTS4 in Cancer and Angiogenesis. We demonstrate that full-length ADAMTS4 or its catalytically more active N-terminal 53 kDa autocatalytic fragment both promote B16 melanoma growth and angiogenesis in mice. In contrast, overexpression of its catalytically-inactive E362A mutant or truncated fragments containing only the C-terminal ancillary domains suppresses melanoma growth and angiogenesis under similar conditions. Structure-function mapping revealed that the single TSR domain is essential and sufficient for the anti-tumorigenic activity displayed by the catalytically-inactive ADAMTS4 isoforms. We identified and demonstrated the presence of novel proteolytic fragments of ADAMTS4 containing essentially only the C-terminal ancillary domains in cultured cells. We have confirmed these findings are relevant in a human cancer context as well with an alternative model. ADAMTS-4 also promoted B16 melanoma lung metastasis in an enzyme-dependent manner.
URI: http://scholarbank.nus.edu.sg/handle/10635/43523
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