Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence.
Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence.
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DOI：
10.1038/s41598-021-01012-z
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发表时间：
2021-11-02
影响因子：
4.6
通讯作者：
Jat PS
中科院分区：
文献类型：
--
作者：
Kumari R;Hummerich H;Shen X;Fischer M;Litovchick L;Mittnacht S;DeCaprio JA;Jat PS
细胞衰老是正常细胞在有限次数的分裂后，响应于各种内在和外在刺激而经历的稳定的细胞周期停滞。虽然衰老主要是由p53/p21 WAF 1/CIP 1和pRB/p16 INK 4A肿瘤抑制途径建立和维持的，但负责生长停滞稳定性的下游靶点尚不清楚。我们采用了一个稳定的衰老旁路试验在有条件永生化的人乳腺成纤维细胞（CL 3EcoR）调查的梦想复合物及其相关成分在衰老中的作用。DREAM是一种多亚基复合物，由MuvB核心组成，含有LIN 9、LIN 37、LIN 52、LIN 54和RBBP 4，当与p130（一种RB 1样蛋白）和E2 F4结合时，可抑制细胞周期依赖性基因表达，从而阻止细胞分裂。LIN 52在丝氨酸28处的磷酸化是DREAM组装所需的。p130磷酸化后重新进入细胞周期导致DREAM复合物和MuvB核心的破坏，最初与B-MYB结合，后来与FOXM 1结合，分别形成MMB和MMB-FOXM 1复合物。在这里，我们报告说，同时表达MMB-FOXM 1复合物组分有效地绕过衰老与LIN 52，B-MYB，FOXM 1作为关键组分。此外，衰老的旁路需要非磷酸化的LIN 52，其破坏DREAM复合物，从而表明DREAM复合物在衰老中的组装的中心作用。
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.
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影响因子：
14.9
作者：
Fischer M;Grossmann P;Padi M;DeCaprio JA
通讯作者：
DeCaprio JA
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS
影响因子：
3.3
作者：
Hardy, K;Mansfield, L;Jat, PS
通讯作者：
Jat, PS
影响因子：
50.3
作者：
Rowland, BD;Denissov, SG;Peeper, DS
通讯作者：
Peeper, DS
DOI：
10.1073/pnas.98.2.646
发表时间：
2001-01-16
影响因子：
11.1
作者：
O'Hare, MJ;Bond, J;Jat, PS
通讯作者：
Jat, PS