IngentaConnect von Willebrand factor type D domain mutant of SVS-1/SUSD2, vWDm, ...

Authors: Sugahara, Tetsuo¹; Yamashita, Yzumi¹; Shinomi, Masahito¹; Isobe, Yumiko¹; Yamanoha, Banri²; Iseki, Hiroyoshi³; Takeda, Akihiko³; Okazaki, Yasushi; Kawai, Kenji⁴; Suemizu, Hiroshi⁴; Andoh, Toshiwo

Source: Cancer Science, Volume 98, Number 6, June 2007 , pp. 909-915(7)

Publisher: Blackwell Publishing

Abstract:

SVS-1/SUSD2 is a novel gene, which inhibits growth and reverses tumorigenic phenotypes of cancer cells in vitro. Here we report identification of a mutant of SVS-1, designated SVS-1-vWD^m, in which conserved amino acids GLLG at positions 591-594 in von Willebrand factor type D (vWD) domain are replaced by AAAA. As observed by laser confocal microscope, intracellular localization of the mutant protein has changed such that both the N-terminus and the C-terminus of SVS-1-vWD^m were localized in the inner surface of the plasma membrane, whereas the N-terminus of SVS-1 was localized in the outer surface of the plasma membrane. Additionally, SVS-1-vWD^m was processed much less efficiently and in a slightly different manner. In in vitro studies, adenovirus-mediated transduction of the SVS-1-vWD^mgene induced growth suppression of HeLa cells in a dose-dependent manner, as the wild-type gene and inhibition of anchorage-independent growth. Of great interest is the finding that the mutant protein, vWD^m, but not the wild-type one induced apoptosis, as observed by nuclear as well as DNA fragmentation. Activation of caspase-3 and -9, but not caspase-8 or -12, was also demonstrated in vWD^m-expressing cells. An inhibition of Akt phosphorylation, a major survival signaling component, also occurred in vWD^m-expressing HeLa cells. Together these data suggest that vWD^m induces apoptosis by inactivation of survival signaling component Akt and activation of caspase cascade (mitochondrial pathway) in HeLa cells. We propose SVS-1-vWD^mas an alternative gene for use in developing new therapeutic strategies for the treatment of cancer. (Cancer Sci 2007; 98: 909-915)

Document Type: Research article

DOI: 10.1111/j.1349-7006.2007.00467.x

Affiliations: 1: Department of Bioinformatics and 2: Department of Environmental Engineering for Symbiosis, Faculty of Engineering, Soka University, Tokyo 192-8577; 3: Department of Surgery and Surgical Oncology, Saitama Medical University, Moroyama-cho, Iruma-gun, Saitama 350-0495; 4: Biomedical Research Department, Central Institute for Experimental Animals, Kawasaki 216-0001, Japan

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von Willebrand factor type D domain mutant of SVS-1/SUSD2, vWDm, induces apoptosis in HeLa cells

von Willebrand factor type D domain mutant of SVS-1/SUSD2, vWD^m, induces apoptosis in HeLa cells