Lamin B1 fluctuations have differential effects on cellular proliferation and senescence
Oliver Dreesen,Alexandre Chojnowski,Peh Fern Ong,Tian Yun Zhao,John E.A. Common,Declan P. Lunny,E. Birgitte Lane,Shu Jin Lee,Leah A. Vardy,Colin L. Stewart,Alan Colman +10 more
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Both LMNB1 depletion and overexpression inhibit proliferation, but onlyLMNB1 overexpressed induces senescence.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.read more
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