Elastic fibres are essential for normal physiology in numerous tissues, including arteries, lungs and skin. Fibulin-4 is an elastic-fibre-associated glycoprotein that is indispensable for elastic-fibre formation in mice. However, the mechanism by which fibulin-4 executes this function remains to be determined. Here, we established an in vitro functional assay system in which fibulin-4 was knocked down in human foreskin fibroblasts using siRNA (small interfering RNA) technology. With two different siRNAs, substantial knockdown of fibulin-4 was achieved, and this suppression was associated with impaired elastic-fibre formation by the fibroblasts. Real-time reverse transcription–PCR analysis showed that knockdown of fibulin-4 expression was accompanied by reduced expression of tropoelastin mRNA. Further analysis showed that this decrease was caused by transcriptional down-regulation of tropoelastin. This effect was selective, since the mRNA level of other elastic-fibre-associated proteins, including fibrillin-1, lysyl oxidase and lysyl oxidase-like-1, was not affected. Moreover, addition of conditioned medium from cultures of CHO (Chinese-hamster ovary) cells overexpressing fibulin-4 stimulated tropoelastin expression and elastic-fibre formation in cultures of Williams–Beuren-syndrome fibroblasts. Knocking down or knocking out fibulin-4 in mice led to a decrease in tropoelastin expression in the aorta. These results indicate that fibulin-4, considered as a structural protein, may also participate in regulating elastic-fibre formation in human cells through an unanticipated mechanism, namely the regulation of tropoelastin expression.
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Research Article|
September 14 2009
Fibulin-4 regulates expression of the tropoelastin gene and consequent elastic-fibre formation by human fibroblasts
Qiuyun Chen;
Qiuyun Chen
1
*Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
1To whom correspondence should be addressed (email chenq3@ccf.org).
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Teng Zhang;
Teng Zhang
*Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Joseph F. Roshetsky;
Joseph F. Roshetsky
*Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Zhufeng Ouyang;
Zhufeng Ouyang
*Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Jeroen Essers;
Jeroen Essers
†Department of Cell Biology and Genetics, Erasmus MC, Dr. Molewaterplein 50, 3015GE, Rotterdam, The Netherlands
‡Department of Radiation Oncology, Erasmus MC, Dr. Molewaterplein 50, 3015GE, Rotterdam, The Netherlands
§Department of Vascular Surgery, Erasmus MC, Dr. Molewaterplein 50, 3015GE, Rotterdam, The Netherlands
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Chun Fan;
Chun Fan
*Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Qing Wang;
Qing Wang
*Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Aleksander Hinek;
Aleksander Hinek
¶Cardiovascular Research, Heart Centre, Hospital for Sick Children and Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada, M5G 1X8
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Edward F. Plow;
Edward F. Plow
*Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, U.S.A.
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Paul E. Dıcorleto
Paul E. Dıcorleto
∥Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Cleveland, OH 44195, U.S.A.
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Publisher: Portland Press Ltd
Received:
June 30 2009
Accepted:
July 23 2009
Accepted Manuscript online:
July 23 2009
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2009 Biochemical Society
2009
Biochem J (2009) 423 (1): 79–89.
Article history
Received:
June 30 2009
Accepted:
July 23 2009
Accepted Manuscript online:
July 23 2009
Citation
Qiuyun Chen, Teng Zhang, Joseph F. Roshetsky, Zhufeng Ouyang, Jeroen Essers, Chun Fan, Qing Wang, Aleksander Hinek, Edward F. Plow, Paul E. Dıcorleto; Fibulin-4 regulates expression of the tropoelastin gene and consequent elastic-fibre formation by human fibroblasts. Biochem J 1 October 2009; 423 (1): 79–89. doi: https://doi.org/10.1042/BJ20090993
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