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

Eva Latorre; Vishal Birar; Angela Sheerin; Charles C. Jeynes; Amy Hooper; Helen Dawe; David Melzer; Lynne Cox; Richard Faragher; Elizabeth Ostler; Lorna W. Harries

doi:10.1186/s12860-017-0147-7

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

Eva Latorre, Vishal Birar, Angela Sheerin, Charles C. Jeynes, Amy Hooper, Helen Dawe, David Melzer, Lynne Cox, Richard Faragher, Elizabeth Ostler, Lorna W. Harries

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Altered 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. Results: Treatment 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. Conclusions: This 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.

Original language	English
Article number	31
Pages (from-to)	1-15
Number of pages	15
Journal	BMC Cell Biology
Volume	18
DOIs	https://doi.org/10.1186/s12860-017-0147-7
Publication status	Published - 17 Oct 2017

Bibliographical note

© The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Keywords

Alternative splicing
Ageing
Resveratrol
Senescence
Fibroblasts

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Richard Faragher
- R.G.A.Faragherbrighton.acuk
- School of Applied Sciences - Professor of Biogerontology
- Centre for Lifelong Health
Person: Academic
Angela Sheerin
- A.N.Sheerinbrighton.acuk
- School of Applied Sciences - Principal Lecturer
- Centre for Lifelong Health
Person: Academic

Cite this

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title = "Small molecule modulation of splicing factor expression is associated with rescue from cellular senescence",

abstract = "Background: Altered 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. Results: Treatment 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. Conclusions: This 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.",

keywords = "Alternative splicing, Ageing, Resveratrol, Senescence, Fibroblasts",

author = "Eva Latorre and Vishal Birar and Angela Sheerin and Jeynes, {Charles C.} and Amy Hooper and Helen Dawe and David Melzer and Lynne Cox and Richard Faragher and Elizabeth Ostler and Harries, {Lorna W.}",

note = "{\textcopyright} The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.",

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doi = "10.1186/s12860-017-0147-7",

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AU - Latorre, Eva

AU - Birar, Vishal

AU - Sheerin, Angela

AU - Jeynes, Charles C.

AU - Hooper, Amy

AU - Dawe, Helen

AU - Melzer, David

AU - Cox, Lynne

AU - Faragher, Richard

AU - Ostler, Elizabeth

AU - Harries, Lorna W.

N1 - © The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

PY - 2017/10/17

Y1 - 2017/10/17

N2 - Background: Altered 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. Results: Treatment 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. Conclusions: This 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.

AB - Background: Altered 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. Results: Treatment 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. Conclusions: This 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.

KW - Alternative splicing

KW - Ageing

KW - Resveratrol

KW - Senescence

KW - Fibroblasts

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DO - 10.1186/s12860-017-0147-7

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JO - BMC Cell Biology

JF - BMC Cell Biology

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

Abstract

Bibliographical note

Keywords

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Richard Faragher

Angela Sheerin

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