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.
© 2021. The Author(s).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Breast / cytology
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Breast / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cellular Senescence*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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E2F Transcription Factors / genetics
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E2F Transcription Factors / metabolism
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Female
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Fibroblasts / cytology
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Fibroblasts / metabolism*
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Forkhead Box Protein M1 / genetics
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Forkhead Box Protein M1 / metabolism*
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Gene Expression Regulation*
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Humans
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Kv Channel-Interacting Proteins / genetics
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Kv Channel-Interacting Proteins / metabolism
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Phosphorylation
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Retinoblastoma Binding Proteins / genetics
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Retinoblastoma Binding Proteins / metabolism
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Trans-Activators / genetics
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Trans-Activators / metabolism*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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YAP-Signaling Proteins / genetics
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YAP-Signaling Proteins / metabolism
Substances
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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E2F Transcription Factors
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FOXM1 protein, human
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Forkhead Box Protein M1
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KCNIP3 protein, human
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Kv Channel-Interacting Proteins
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MYBL2 protein, human
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Multiprotein Complexes
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RB1 protein, human
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Repressor Proteins
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Retinoblastoma Binding Proteins
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TP53 protein, human
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Trans-Activators
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Tumor Suppressor Protein p53
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YAP-Signaling Proteins
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YAP1 protein, human
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Ubiquitin-Protein Ligases