Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Altered expression of proteins in the dystrophin-associated glycoprotein complex results in muscular dystrophy and has more recently been implicated in a number of forms of cancer. Here we show that loss of either of two members of this complex, dystrophin in mdx mice or alpha sarcoglycan in Sgca(-/-) mice, results in the spontaneous development of muscle-derived embryonal rhabdomyosarcoma (RMS) after 1 year of age. Many mdx and Sgca(-/-) tumors showed increased expression of insulin-like growth factor 2, retinoblastoma protein, and phosphorylated Akt and decreased expression of phosphatase and tensin homolog gene, much as is found in a human RMS. Further, all mdx and Sgca(-/-) RMS analyzed had increased expression of p53 and murine double minute (mdm)2 protein and contained missense p53 mutations previously identified in human cancers. The mdx RMS also contained missense mutations in Mdm2 or alternatively spliced Mdm2 transcripts that lacked an exon encoding a portion of the p53-binding domain. No Pax3:Fkhr or Pax7:Fkhr translocation mRNA products were evident in any tumor. Expression of natively glycosylated alpha dystroglycan and alpha sarcoglycan was reduced in mdx RMS, whereas dystrophin expression was absent in almost all human RMS, both for embryonal and alveolar RMS subtypes. These studies show that absence of members of the dystrophin-associated glycoprotein complex constitutes a permissive environment for spontaneous development of embryonal RMS associated with mutation of p53 and mutation or altered splicing of Mdm2.
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PMID:Mice lacking dystrophin or alpha sarcoglycan spontaneously develop embryonal rhabdomyosarcoma with cancer-associated p53 mutations and alternatively spliced or mutant Mdm2 transcripts. 2001 82

We have previously reported that mice with muscular dystrophy, including mdx mice, develop embryonal rhabdomyosarcoma (eRMS) with a low incidence after 1 year of age and that almost all such tumours contain cancer-associated p53 mutations. To further demonstrate the relevance of p53 inactivation, we created p53-deficient mdx mice. Here we demonstrate that loss of one or both p53 (Trp53) alleles accelerates eRMS incidence in the mdx background, such that almost all Trp53(-/-) mdx animals develop eRMS by 5 months of age. To ascertain whether increased tumour incidence was due to the regenerative microenvironment found in dystrophic skeletal muscles, we induced muscle regeneration in Trp53(+/+) and Trp53(-/-) animals using cardiotoxin (Ctx). Wild-type (Trp53(+/+) ) animals treated with Ctx, either once every 7 days or once every 14 days from 1 month of age onwards, developed no eRMS; however, all similarly Ctx-treated Trp53(-/-) animals developed eRMS by 5 months of age at the site of injection. Most of these tumours displayed markers of human eRMS, including over-expression of Igf2 and phosphorylated Akt. These data demonstrate that the presence of a regenerative microenvironment in skeletal muscle, coupled with Trp53 deficiency, is sufficient to robustly induce eRMS in young mice. These studies further suggest that consideration should be given to the potential of the muscle microenvironment to support tumourigenesis in regenerative therapies for myopathies.
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PMID:Induction of a regenerative microenvironment in skeletal muscle is sufficient to induce embryonal rhabdomyosarcoma in p53-deficient mice. 2191 58