Abstract
The nuclear lamina consists of A- and B-type lamins. Mutations in LMNA cause many human diseases, including progeria, a premature aging syndrome, whereas LMNB1 duplication causes adult-onset autosomal dominant leukodystrophy (ADLD). LMNB1 is reduced in cells from progeria patients, but the significance of this reduction is unclear. In this paper, we show that LMNB1 protein levels decline in senescent human dermal fibroblasts and keratinocytes, mediated by reduced transcription and inhibition of LMNB1 messenger ribonucleic acid (RNA) translation by miRNA-23a. This reduction is also observed in chronologically aged human skin tissue. To determine whether altered LMNB1 levels cause senescence, we either increased or reduced LMNB1. Both LMNB1 depletion and overexpression inhibited proliferation, but only LMNB1 overexpression induced senescence, which was prevented by telomerase expression or inactivation of p53. This phenotype was exacerbated by a simultaneous reduction of LMNA/C. Our results demonstrate that altering LMNB1 levels inhibits proliferation and are relevant to understanding the molecular pathology of ADLD.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation
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Cell Proliferation*
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Cells, Cultured
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Cellular Senescence*
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DNA Damage
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DNA-Binding Proteins / metabolism
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Down-Regulation
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Genotype
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Humans
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Keratinocytes / metabolism*
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Keratinocytes / pathology
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Lamin Type A / metabolism
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Lamin Type B / genetics
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Lamin Type B / metabolism*
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Membrane Proteins / metabolism
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MicroRNAs / metabolism
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Nuclear Lamina / metabolism
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Pelizaeus-Merzbacher Disease / genetics
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Pelizaeus-Merzbacher Disease / metabolism
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Pelizaeus-Merzbacher Disease / pathology
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Phenotype
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RNA Interference
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RNA, Messenger / metabolism
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Skin Aging
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Telomerase / metabolism
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Time Factors
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Transcription, Genetic
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Transfection
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Tumor Suppressor Protein p53 / metabolism
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Up-Regulation
Substances
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DNA-Binding Proteins
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LMNA protein, human
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Lamin Type A
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Lamin Type B
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MIRN23a microRNA, human
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Membrane Proteins
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MicroRNAs
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RNA, Messenger
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TP53 protein, human
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Tumor Suppressor Protein p53
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lamina-associated polypeptide 2
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TERT protein, human
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Telomerase
Supplementary concepts
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Leukodystrophy, Demyelinating, Adult-Onset, Autosomal Dominant