Publication Date:
2013-09-13
Description:
Down's syndrome results from full or partial trisomy of chromosome 21. However, the consequences of the underlying gene-dosage imbalance on adult tissues remain poorly understood. Here we show that in Ts65Dn mice, which are trisomic for 132 genes homologous to genes on human chromosome 21, triplication of Usp16 reduces the self-renewal of haematopoietic stem cells and the expansion of mammary epithelial cells, neural progenitors and fibroblasts. In addition, Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in Ts65Dn fibroblasts. Usp16 can remove ubiquitin from histone H2A on lysine 119, a critical mark for the maintenance of multiple somatic tissues. Downregulation of Usp16, either by mutation of a single normal Usp16 allele or by short interfering RNAs, largely rescues all of these defects. Furthermore, in human tissues overexpression of USP16 reduces the expansion of normal fibroblasts and postnatal neural progenitors, whereas downregulation of USP16 partially rescues the proliferation defects of Down's syndrome fibroblasts. Taken together, these results suggest that USP16 has an important role in antagonizing the self-renewal and/or senescence pathways in Down's syndrome and could serve as an attractive target to ameliorate some of the associated pathologies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816928/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816928/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adorno, Maddalena -- Sikandar, Shaheen -- Mitra, Siddhartha S -- Kuo, Angera -- Nicolis Di Robilant, Benedetta -- Haro-Acosta, Veronica -- Ouadah, Youcef -- Quarta, Marco -- Rodriguez, Jacqueline -- Qian, Dalong -- Reddy, Vadiyala M -- Cheshier, Samuel -- Garner, Craig C -- Clarke, Michael F -- CA100225/CA/NCI NIH HHS/ -- CA154209/CA/NCI NIH HHS/ -- R01 CA100225/CA/NCI NIH HHS/ -- R01 CA104987/CA/NCI NIH HHS/ -- T32 CA009302/CA/NCI NIH HHS/ -- U01 CA154209/CA/NCI NIH HHS/ -- England -- Nature. 2013 Sep 19;501(7467):380-4. doi: 10.1038/nature12530. Epub 2013 Sep 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24025767" target="_blank"〉PubMed〈/a〉
Keywords:
Adult Stem Cells/metabolism/pathology
;
Animals
;
Cell Aging
;
Cell Proliferation
;
Chromosomes, Human, Pair 21/genetics
;
Cyclin-Dependent Kinase Inhibitor p16/metabolism
;
Disease Models, Animal
;
Down Syndrome/genetics/*metabolism/*pathology
;
Epithelium/metabolism
;
Female
;
Fibroblasts/cytology/metabolism/pathology
;
Gene Dosage
;
Gene Expression Regulation
;
Hematopoietic Stem Cells/cytology/pathology
;
Humans
;
Mammary Glands, Animal/cytology/metabolism
;
Mice
;
Molecular Targeted Therapy
;
Neural Stem Cells/*metabolism/*pathology
;
Trisomy/genetics
;
Ubiquitin Thiolesterase/genetics/*metabolism
;
Ubiquitination
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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