Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence

BMC Cell Biology

Research Article

J. Charles C. Jeynes¹  Helen R. Dawe²  Lynne S. Cox³  Eva Latorre⁴  Lorna W. Harries⁴  Amy Hooper⁴  David Melzer⁴  Vishal C. Birar⁵  Angela N. Sheerin⁵  Richard G. A. Faragher⁵  Elizabeth L. Ostler⁵ 

[1] Centre for Biomedical Modelling and Analysis, University of Exeter, EX2 5DW, Exeter, Devon, UK;College of Life and Environmental Sciences, University of Exeter, EX4 4QD, Exeter, Devon, UK;Department of Biochemistry, University of Oxford, OX1 3QU, Oxford, UK;Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, University of Exeter, Barrack Road, EX2 5DW, Exeter, Devon, UK;School of Pharmacy and Biomolecular Sciences, University of Brighton, Cockcroft Building, Moulsecoomb, BN2 4GJ, Brighton, UK;

关键词: Alternative splicing;    Ageing;    Resveratrol;    Senescence;    Fibroblasts;   

DOI  :  10.1186/s12860-017-0147-7

 received in 2017-07-10, accepted in 2017-10-09,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundAltered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.ResultsTreatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists.ConclusionsThis is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.

【 授权许可】

CC BY   
© The Author(s). 2017