Loycano Michael A, Pienta Kenneth J, Amend Sarah R
Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Cancer Ecology Center, James Buchanan Brady Urological Institute, Johns Hopkins Medical Institute, Baltimore, MD, USA; Cellular and Molecular Medicine Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Cancer Lett. 2025 Mar 31;613:217526. doi: 10.1016/j.canlet.2025.217526. Epub 2025 Feb 3.
High Myc phenotypes are extensively documented in the hyperproliferative cell cycle of cancer cells, as well as non-proliferative endoreplication cycles engaged during normal development and stress response. Notably, endoreplication in cancer produces chemotherapy resistant polyploid cells, necessitating a clearer understanding of altered cell cycle regulation that uncouples DNA replication and mitotic cell division. The c-Myc oncogene is a well-established transcriptional regulator of cell cycle progression and has been extensively published as an essential driver of the G1/S transition. Beyond S phase, Myc transcriptionally activates the proteins that drive mitotic entry. Sustained activation of Myc through the cell cycle transcriptionally couples DNA replication and mitotic cell division. Based on the literature in this field, we propose a new model of temporal regulation of Myc activity that serves to either couple or uncouple these two processes, determining cell cycle fate - proliferation or polyploidy. The mitotic cell cycle requires two pulses of Myc activity - the first driving the G1/S transition and the second driving the G2/M transition. During mitosis, Myc activity must be silenced to achieve high-fidelity division. Absence of the second activity pulse during G2 results in the downregulation of the proteins essential for mitotic entry and permits premature activation of APC/C, inducing mitotic bypass. A subsequent rise of Myc activity following mitotic bypass permits genome re-replication, driving polyploid phenotypes. This model serves to provide a new level of understanding to the global regulation of S phase-mitosis coupling, as well as a new lens to view low Myc phenotypes.
高Myc表型在癌细胞的过度增殖细胞周期以及正常发育和应激反应过程中进行的非增殖性核内复制周期中都有广泛记录。值得注意的是，癌症中的核内复制会产生对化疗耐药的多倍体细胞，因此有必要更清楚地了解改变的细胞周期调控，这种调控会使DNA复制和有丝分裂细胞分裂脱钩。c-Myc癌基因是细胞周期进程中公认的转录调节因子，并且已被广泛报道为G1/S期转换的关键驱动因素。在S期之后，Myc转录激活驱动有丝分裂进入的蛋白质。通过细胞周期持续激活Myc会在转录水平上使DNA复制和有丝分裂细胞分裂耦合。基于该领域的文献，我们提出了一种Myc活性的时间调控新模型，该模型用于耦合或解耦这两个过程，从而决定细胞周期命运——增殖或多倍体化。有丝分裂细胞周期需要两个脉冲的Myc活性——第一个驱动G1/S期转换，第二个驱动G2/M期转换。在有丝分裂期间，Myc活性必须被沉默以实现高保真分裂。G2期缺乏第二个活性脉冲会导致有丝分裂进入所必需的蛋白质下调，并允许APC/C过早激活，从而诱导有丝分裂旁路。有丝分裂旁路后Myc活性的随后升高允许基因组重新复制，从而驱动多倍体表型。该模型有助于为S期-有丝分裂耦合的全局调控提供新的理解层面，也为观察低Myc表型提供了新的视角。
