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

Kumari, R., Hummerich, H., Shen, X., Fischer, M., Litovchick, L., Mittnacht, S., DeCaprio, J. A. and Jat, P. S. (2021) Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence. Scientific Reports, 11, 21506. (doi: 10.1038/s41598-021-01012-z) (PMID:34728711) (PMCID:PMC8563780)

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.

• Item Type: Articles
• Additional Information: RK was supported by a Commonwealth Scholarship Commission PhD scholarship (INCS-2014-212). XS is the recipient of a UCL Overseas Research Scholarship (ORS) and a Graduate Research Scholarship (GRS) excellence award. LL was supported by NIH R21DE029927 and R01CA188571. MF was supported through the German Research Foundation (DFG; Grant FI 1993/2-1). JAD was supported in part by the US Public Health Service Grants R35CA232128 and P01CA203655. JAD has also received research support from Rain Therapeutics.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Kumari, Dr Ruchi
• Authors: Kumari, R., Hummerich, H., Shen, X., Fischer, M., Litovchick, L., Mittnacht, S., DeCaprio, J. A., and Jat, P. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Scientific Reports 11:21506
• Publisher Policy: Reproduced under a Creative Commons License