Abstract
Endogenous genes regulated by telomere length have not previously been identified in human cells. Here we show that telomere length regulates the expression of interferon stimulated gene 15 (ISG15, 1p36.33). ISG15 expression (RNA and protein) increases in human cells with short telomeres, and decreases following the elongation of telomeres by human telomerase reverse transcriptase (hTERT). The short-telomere-dependent up-regulation of ISG15 is not mediated by replicative senescence/DNA damage signaling or type I interferons. In human skin specimens obtained from various aged individuals, ISG15 is up-regulated in a subset of cells in older individuals. Our results demonstrate that endogenous human genes can be regulated by the length of telomeres prior to the onset of DNA damage signals, and suggest the possibility that cell turnover/telomere shortening may provide a mechanism for adjusting cellular physiology. The upregulation of ISG15 with telomere shortening may contribute to chronic inflammatory states associated with human aging.
Keywords:
ISG15; aging; cancer; cell turnover; inflammation; telomere position effect.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Aged
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Aging / metabolism
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Agrin / genetics
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Antibodies / immunology
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Antibodies / pharmacology
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Cell Line
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Cellular Senescence / physiology
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cytokines / genetics
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Cytokines / metabolism*
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DNA Damage / physiology
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Epithelial Cells / metabolism
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Fibroblasts / metabolism
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Gene Expression / genetics
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Gene Expression Regulation / physiology*
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Histones / metabolism
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Humans
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Infant
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Interferon-beta / genetics
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Interferon-beta / immunology
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Middle Aged
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Oligonucleotide Array Sequence Analysis
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RNA Interference
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Signal Transduction / physiology
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Telomerase / genetics
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Telomerase / metabolism
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Telomere / physiology*
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Transfection
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Tumor Suppressor Protein p53 / genetics
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Ubiquitins / genetics
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Ubiquitins / metabolism*
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Up-Regulation / genetics
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Young Adult
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beta-Galactosidase / metabolism
Substances
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Agrin
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Antibodies
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cytokines
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H2AX protein, human
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Histones
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Tumor Suppressor Protein p53
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Ubiquitins
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ISG15 protein, human
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Interferon-beta
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Telomerase
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beta-Galactosidase