Molano-Fernández Maria, Hickson Ian D, Herranz Héctor
Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
Department of Cellular and Molecular Medicine, Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark.
Front Cell Dev Biol. 2023 Jan 10;10:992253. doi: 10.3389/fcell.2022.992253. eCollection 2022.
The regulation of the cell division cycle is governed by a complex network of factors that together ensure that growing or proliferating cells maintain a stable genome. Defects in this system can lead to genomic instability that can affect tissue homeostasis and thus compromise human health. Variations in ploidy and cell heterogeneity are observed frequently in human cancers. Here, we examine the consequences of upregulating the cell cycle regulator Cyclin E in the male accessory gland. The accessory gland is the functional analog of the human prostate. This organ is composed of a postmitotic epithelium that is emerging as a powerful system for modelling different aspects of tumor initiation and progression. We show that Cyclin E upregulation in this model is sufficient to drive tissue dysplasia. Cyclin E overexpression drives endoreplication and affects DNA integrity, which results in heterogeneous nuclear and cellular composition and variable degrees of DNA damage. We present evidence showing that, despite the presence of genotoxic stress, those cells are resistant to apoptosis and thus defective cells are not eliminated from the tissue. We also show that Cyclin E-expressing cells in the accessory gland display mitochondrial DNA aggregates that colocalize with Cyclin E protein. Together, the findings presented here show that Cyclin E upregulation in postmitotic cells of the accessory gland organ causes cellular defects such as genomic instability and mitochondrial defects, eventually leading to tissue dysplasia. This study highlights novel mechanisms by which Cyclin E might contribute to disease initiation and progression.
细胞分裂周期的调控由一个复杂的因子网络控制，这些因子共同确保生长或增殖的细胞维持基因组的稳定。该系统的缺陷会导致基因组不稳定，进而影响组织稳态，从而损害人类健康。在人类癌症中经常观察到倍性和细胞异质性的变化。在这里，我们研究了上调雄性附属性腺中细胞周期调节因子细胞周期蛋白E的后果。附属性腺是人类前列腺的功能类似物。这个器官由有丝分裂后上皮组成，正成为一个强大的系统，用于模拟肿瘤发生和进展的不同方面。我们表明，在这个模型中上调细胞周期蛋白E足以驱动组织发育异常。细胞周期蛋白E的过表达驱动核内复制并影响DNA完整性，这导致核和细胞组成的异质性以及不同程度的DNA损伤。我们提供的证据表明，尽管存在基因毒性应激，但这些细胞对凋亡具有抗性，因此缺陷细胞不会从组织中被清除。我们还表明，附属性腺中表达细胞周期蛋白E的细胞显示出线粒体DNA聚集体，其与细胞周期蛋白E蛋白共定位。总之，这里呈现的研究结果表明，附属性腺器官有丝分裂后细胞中细胞周期蛋白E的上调会导致细胞缺陷，如基因组不稳定和线粒体缺陷，最终导致组织发育异常。这项研究突出了细胞周期蛋白E可能促成疾病发生和进展的新机制。
