Identification of Ubiquitin Ligases Required for Skeletal Muscle Atrophy

American Association for the Advancement of Science (AAAS) - Tập 294 Số 5547 - Trang 1704-1708 - 2001
Sue C. Bodine1, Esther Latres1, Susanne Baumhueter2, Venus Lai1, Lorna Nuñez1, Brian Clarke1, William Poueymirou1, Frank J. Panaro1, Erqian Na1, Kumar Dharmarajan1, Zhen‐Qiang Pan3, David M. Valenzuela1, Thomas M. DeChiara1, Trevor N. Stitt1, George D. Yancopoulos1, David J. Glass1
1Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY, 10591–6707, USA.
2Applied Biosystems, 850 Lincoln Center Drive, Foster City, CA, 94404 USA
3Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, NY, 10029–6574, USA.

Tóm tắt

Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 ( MuRF1 ), and a gene we designate Muscle Atrophy F-box ( MAFbx ), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.

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Tài liệu tham khảo

10.1097/00075197-200105000-00003

C. Rommel et al. Nature Cell Biol. 3 1009 (2001).

S. C. Bodine et al. Nature Cell Biol. 3 1013 (2001).

Additional data and methods used in this study are described in the supplementary Web material available on Science Online at www.sciencemag.org/cgi/content/full/1065874/DC1. GenBank accession numbers are as follows: rat MAFbx ; human MAFbx ; and rat MuRF1 . For Northern methods and probe details ref. (2) of Web material. Knockouts were done with the proprietary Velocigene technology which allows for the rapid and high-throughput generation of custom gene mutations in mice (T. M. De Chiara W. T. Poueymirou D. M. Valenzuela G. D. Yancopoulos unpublished data).

10.1097/00024382-199701000-00001

10.1016/S0021-9258(18)93117-0

10.1016/S0092-8674(00)80403-1

J. Lisztwan et al. EMBO J. 17 368 (1998).

10.1016/S0960-9822(00)80021-4

C. Cenciarelli et al. Curr. Biol. 9 1177 (1999).

L. Nunez D. J. Glass unpublished data.

E. T. Kipreos M. Pagano Genome Biol. 1 3002.1 (2000).

T.-C. He et al. Proc. Natl. Acad. Sci. U.S.A. 95 2509 (1998).

Bains W., Ponte P., Blau H. M., Kedes L., Mol. Cell. Biol. 4, 1449 (1984).

T. Centner et al. J. Mol. Biol. 306 717 (2001).

10.1016/S0960-9822(00)00287-6

10.1016/S0092-8674(00)00077-5

10.1152/jappl.1987.63.1.130

A. Chen et al. J. Biol. Chem. 275 15432 (2000).

We thank L. S. Schleifer and P. R. Vagelos for their enthusiastic support; E. Burrows B. Efraim and V. Lan for expert graphics work; and M. Gonzalez for insightful discussions. We thank members of the Muscle in vivo and in vitro groups transgenic group and tissue culture group for their expert technical assistance.

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American Association for the Advancement of Science (AAAS)

Tập 294 Số 5547

1704-1708

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