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J. Biol. Chem., Vol. 280, Issue 51, 42397-42404, December 23, 2005

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Proteomic Analysis of Vascular Endothelial Growth Factor-induced Endothelial Cell Differentiation Reveals a Role for Chloride Intracellular Channel 4 (CLIC4) in Tubular Morphogenesis^*

Svante Bohman1, Taro Matsumoto2, Kwang Suh, Anna Dimberg3, Lars Jakobsson, Stuart Yuspa, and Lena Claesson-Welsh4

From the Department of Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, S-751 85 Uppsala, Sweden and the Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892

Formation of new vessels from pre-existing capillaries demands extensive reprogramming of endothelial cells through transcriptional and post-transcriptional events. We show that 120 protein spots in a two-dimensional isoelectric focusing/electrophoretic analysis were affected during vascular endothelial growth factor-A-induced endothelial cell tubular morphogenesis in vitro, as a result of changes in charge or expression level of the corresponding proteins. For about 22% of the spots, the protein products could be identified, of which several previously have been implicated in cytoskeletal reorganization and angiogenesis. One such protein was heat shock protein 27, a chaperone involved in -actin rearrangement that was identified as regulated in degree of serine phosphorylation. We also identified regulation of chloride intracellular channel 4 (CLIC4), the expression of which decreased during tubular morphogenesis. CLIC4 was expressed at high levels in resting vessels, whereas expression was modulated during pathological angiogenesis such as in tumor vessels. The subcellular localization of CLIC4 in endothelial cells was dependent on whether cells were engaged in proliferation or tube formation. Antisense- and small interfering RNA-mediated suppression of CLIC4 expression led to arrest in tubular morphogenesis. Our data implicate CLIC4 in formation of a vessel lumen.

Received for publication, June 21, 2005 , and in revised form, October 16, 2005.

^* This work was supported in part by the Swedish Science Council Project K2005-32X-12552-08A (to L. C.-W.), the Swedish Cancer Foundation Project 3820-B01-06XAC, the Novo Nordisk Foundation, and the European Union 6th Framework Integrated Project Lymphangiogenomics, LSHG-CT-2004-503573. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Experimental Procedures and supplemental Fig. S1.

¹ Supported by the Gustaf Adolf Johansson Foundation by the Uppsala University Medical Faculty.

² Present address: Division of Cell Regeneration and Transplantation, Advanced Medical Research Center, Nihon University School of Medicine, 30-1, Ohyaguchikamimachi, Itabashi-ku, Tokyo 173-8610, Japan.

³ Supported by a grant from the Association for International Cancer Research (UK) and by the Swedish Cancer Foundation Project 4828-B03-01PAA.

⁴ To whom correspondence should be addressed: Dept. of Genetics and Pathology, Uppsala University, Dag Hammarskjölds Väg 20, S-751 85 Uppsala, Sweden. Tel.: 4618 4714363; Fax: 4618558931; E-mail: Lena.Welsh{at}genpat.uu.se.

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