Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence
| Autor: | Holger Hummerich, Xu Shen, Martin Fischer, James A. DeCaprio, Ruchi Kumari, Sibylle Mittnacht, Parmjit S. Jat, Larisa Litovchick |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Senescence Cell biology Cell cycle checkpoint Cell division Molecular biology Ubiquitin-Protein Ligases Science Cell Cycle Proteins Article Humans DREAM complex RBBP4 Breast Phosphorylation E2F4 Cellular Senescence Cancer Multidisciplinary Chemistry Forkhead Box Protein M1 Kv Channel-Interacting Proteins YAP-Signaling Proteins Fibroblasts Cell cycle E2F Transcription Factors Repressor Proteins Retinoblastoma Binding Proteins Oncology Gene Expression Regulation Multiprotein Complexes Trans-Activators Medicine Female Tumor Suppressor Protein p53 |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-11 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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