| Down's syndrome suppression of tumour growth and the role of the calcineurin inhibitor DSCR1. | |
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MedLine Citation:
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PMID: 19458618 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The incidence of many cancer types is significantly reduced in individuals with Down's syndrome, and it is thought that this broad cancer protection is conferred by the increased expression of one or more of the 231 supernumerary genes on the extra copy of chromosome 21. One such gene is Down's syndrome candidate region-1 (DSCR1, also known as RCAN1), which encodes a protein that suppresses vascular endothelial growth factor (VEGF)-mediated angiogenic signalling by the calcineurin pathway. Here we show that DSCR1 is increased in Down's syndrome tissues and in a mouse model of Down's syndrome. Furthermore, we show that the modest increase in expression afforded by a single extra transgenic copy of Dscr1 is sufficient to confer significant suppression of tumour growth in mice, and that such resistance is a consequence of a deficit in tumour angiogenesis arising from suppression of the calcineurin pathway. We also provide evidence that attenuation of calcineurin activity by DSCR1, together with another chromosome 21 gene Dyrk1a, may be sufficient to markedly diminish angiogenesis. These data provide a mechanism for the reduced cancer incidence in Down's syndrome and identify the calcineurin signalling pathway, and its regulators DSCR1 and DYRK1A, as potential therapeutic targets in cancers arising in all individuals. |
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Authors:
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Kwan-Hyuck Baek; Alexander Zaslavsky; Ryan C Lynch; Carmella Britt; Yoshiaki Okada; Richard J Siarey; M William Lensch; In-Hyun Park; Sam S Yoon; Takashi Minami; Julie R Korenberg; Judah Folkman; George Q Daley; William C Aird; Zygmunt Galdzicki; Sandra Ryeom |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-05-20 |
Journal Detail:
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Title: Nature Volume: 459 ISSN: 1476-4687 ISO Abbreviation: Nature Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-06-25 Completed Date: 2009-07-02 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 0410462 Medline TA: Nature Country: England |
Other Details:
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Languages: eng Pagination: 1126-30 Citation Subset: IM |
Affiliation:
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Vascular Biology Program, Department of Surgery, Children's Hospital Boston, Massachusetts 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Calcineurin / metabolism Catechols Cells, Cultured Disease Models, Animal Down Syndrome / genetics*, metabolism Endothelial Cells / metabolism Gene Dosage / genetics Humans Inositol / genetics* Intracellular Signaling Peptides and Proteins / genetics*, metabolism* Mice Mice, Transgenic Muscle Proteins / genetics*, metabolism* Protein-Serine-Threonine Kinases / metabolism Protein-Tyrosine Kinases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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R01 CA118374-01A2/CA/NCI NIH HHS; //Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Cancell; 0/Catechols; 0/DSCR1 protein, mouse; 0/Intracellular Signaling Peptides and Proteins; 0/Muscle Proteins; 0/RCAN1 protein, human; 6917-35-7/Inositol; EC 2.7.1.-/Dyrk kinase; EC 2.7.10.1/Protein-Tyrosine Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 3.1.3.16/Calcineurin |
| Comments/Corrections | |
Comment In:
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Clin Genet. 2010 Jul;78(1):35-7
[PMID:
20597922
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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