Affiliation:
1. Neuromuscular Research Department, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
2. Division for Laboratory Animal Science and Genetics, Medical University of Vienna, Himberg, Austria
Abstract
Aberrant expression of dystrophin, utrophin, dysferlin, or calpain-3 was originally identified in muscular dystrophies (MDs). Increasing evidence now indicates that these proteins might act as tumor suppressors in myogenic and non-myogenic cancers. As DNA damage and somatic aneuploidy, hallmarks of cancer, are early pathological signs in MDs, we hypothesized that a common pathway might involve the centrosome. Here, we show that dystrophin, utrophin, dysferlin, and calpain-3 are functional constituents of the centrosome. In myoblasts, lack of any of these proteins caused excess centrosomes, centrosome misorientation, nuclear abnormalities, and impaired microtubule nucleation. In dystrophin double-mutants, these defects were significantly aggravated. Moreover, we demonstrate that also in non-myogenic cells, all four MD-related proteins localize to the centrosome, including the muscle-specific full-length dystrophin isoform. Therefore, MD-related proteins might share a convergent function at the centrosome in addition to their diverse, well-established muscle-specific functions. Thus, our findings support the notion that cancer-like centrosome-related defects underlie MDs and establish a novel concept linking MDs to cancer.
Funder
Austrian Society for Research on Neuromuscular Disorders
Neuromuscular Research Department
Herzfelder’sche Familienstiftung
Austrian Science Research Fund
Publisher
Life Science Alliance, LLC
Subject
Health, Toxicology and Mutagenesis,Plant Science,Biochemistry, Genetics and Molecular Biology (miscellaneous),Ecology