Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence

Abstract Cellular senescence is a stable cell cycle arrest that normal cells undergo after a finite number of divisions, in response to a variety of intrinsic and extrinsic stimuli. Although senescence is largely established and maintained by the p53/p21WAF1/CIP1 and pRB/p16INK4A tumour suppressor p...

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Autores principales:	Ruchi Kumari, Holger Hummerich, Xu Shen, Martin Fischer, Larisa Litovchick, Sibylle Mittnacht, James A. DeCaprio, Parmjit S. Jat
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6e66597928294524a625be5f57918552
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spelling	oai:doaj.org-article:6e66597928294524a625be5f579185522021-11-08T10:50:11ZSimultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence10.1038/s41598-021-01012-z2045-2322https://doaj.org/article/6e66597928294524a625be5f579185522021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-01012-zhttps://doaj.org/toc/2045-2322Abstract Cellular senescence is a stable cell cycle arrest that normal cells undergo after a finite number of divisions, in response to a variety of intrinsic and extrinsic stimuli. Although senescence is largely established and maintained by the p53/p21WAF1/CIP1 and pRB/p16INK4A tumour suppressor pathways, the downstream targets responsible for the stability of the growth arrest are not known. We have employed a stable senescence bypass assay in conditionally immortalised human breast fibroblasts (CL3EcoR) to investigate the role of the DREAM complex and its associated components in senescence. DREAM is a multi-subunit complex comprised of the MuvB core, containing LIN9, LIN37, LIN52, LIN54, and RBBP4, that when bound to p130, an RB1 like protein, and E2F4 inhibits cell cycle-dependent gene expression thereby arresting cell division. Phosphorylation of LIN52 at Serine 28 is required for DREAM assembly. Re-entry into the cell cycle upon phosphorylation of p130 leads to disruption of the DREAM complex and the MuvB core, associating initially to B-MYB and later to FOXM1 to form MMB and MMB-FOXM1 complexes respectively. Here we report that simultaneous expression of MMB-FOXM1 complex components efficiently bypasses senescence with LIN52, B-MYB, and FOXM1 as the crucial components. Moreover, bypass of senescence requires non-phosphorylated LIN52 that disrupts the DREAM complex, thereby indicating a central role for assembly of the DREAM complex in senescence.Ruchi KumariHolger HummerichXu ShenMartin FischerLarisa LitovchickSibylle MittnachtJames A. DeCaprioParmjit S. JatNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ruchi Kumari Holger Hummerich Xu Shen Martin Fischer Larisa Litovchick Sibylle Mittnacht James A. DeCaprio Parmjit S. Jat Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence
description	Abstract Cellular senescence is a stable cell cycle arrest that normal cells undergo after a finite number of divisions, in response to a variety of intrinsic and extrinsic stimuli. Although senescence is largely established and maintained by the p53/p21WAF1/CIP1 and pRB/p16INK4A tumour suppressor pathways, the downstream targets responsible for the stability of the growth arrest are not known. We have employed a stable senescence bypass assay in conditionally immortalised human breast fibroblasts (CL3EcoR) to investigate the role of the DREAM complex and its associated components in senescence. DREAM is a multi-subunit complex comprised of the MuvB core, containing LIN9, LIN37, LIN52, LIN54, and RBBP4, that when bound to p130, an RB1 like protein, and E2F4 inhibits cell cycle-dependent gene expression thereby arresting cell division. Phosphorylation of LIN52 at Serine 28 is required for DREAM assembly. Re-entry into the cell cycle upon phosphorylation of p130 leads to disruption of the DREAM complex and the MuvB core, associating initially to B-MYB and later to FOXM1 to form MMB and MMB-FOXM1 complexes respectively. Here we report that simultaneous expression of MMB-FOXM1 complex components efficiently bypasses senescence with LIN52, B-MYB, and FOXM1 as the crucial components. Moreover, bypass of senescence requires non-phosphorylated LIN52 that disrupts the DREAM complex, thereby indicating a central role for assembly of the DREAM complex in senescence.
format	article
author	Ruchi Kumari Holger Hummerich Xu Shen Martin Fischer Larisa Litovchick Sibylle Mittnacht James A. DeCaprio Parmjit S. Jat
author_facet	Ruchi Kumari Holger Hummerich Xu Shen Martin Fischer Larisa Litovchick Sibylle Mittnacht James A. DeCaprio Parmjit S. Jat
author_sort	Ruchi Kumari
title	Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence
title_short	Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence
title_full	Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence
title_fullStr	Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence
title_full_unstemmed	Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence
title_sort	simultaneous expression of mmb-foxm1 complex components enables efficient bypass of senescence
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6e66597928294524a625be5f57918552
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_version_	1718442625891041280

Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence

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