Dai Yun, Jin Fengyan, Wu Wei, Kumar Shaji K
Laboratory of Cancer Precision Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.
Department of Hematology, Cancer Center, The First Hospital of Jilin University, Changchun, Jilin, China.
Blood Sci. 2019 Sep 17;1(1):34-43. doi: 10.1097/BS9.0000000000000009. eCollection 2019 Aug.
A complex network precisely regulates the cell cycle through the G, S, G, and M phases and is the basis for cell division under physiological and pathological conditions. On the one hand, the transition from one phase to another as well as the progression within each phase is driven by the specific cyclin-dependent kinases (CDKs; e.g., CDK1, CDK2, CDK4, CDK6, and CDK7), together with their exclusive partner cyclins (e.g., cyclin A1, B1, D1-3, and E1). On the other hand, these phases are negatively regulated by endogenous CDK inhibitors such as p16, p18, p19, p21, and p27. In addition, several checkpoints control the commitment of cells to replicate DNA and undergo mitosis, thereby avoiding the passage of genomic errors to daughter cells. CDKs are often constitutively activated in cancer, which is characterized by the uncontrolled proliferation of transformed cells, due to genetic and epigenetic abnormalities in the genes involved in the cell cycle. Moreover, several oncogenes and defective tumor suppressors promote malignant changes by stimulating cell cycle entry and progression or disrupting DNA damage responses, including the cell cycle checkpoints, DNA repair mechanisms, and apoptosis. Thus, genes or proteins related to cell cycle regulation remain the main targets of interest in the treatment of various cancer types, including hematologic malignancies. In this context, advances in the understanding of the cell cycle regulatory machinery provide a basis for the development of novel therapeutic approaches. The present article summarizes the pathways as well as their genetic and epigenetic alterations that regulate the cell cycle; moreover, it discusses the various approved or potential therapeutic targets associated with the cell cycle, focusing on hematologic malignancies.
一个复杂的网络精确地调控细胞周期，使其经历G1、S、G2和M期，这是生理和病理条件下细胞分裂的基础。一方面，细胞从一个阶段过渡到另一个阶段以及在每个阶段内的进程是由特定的细胞周期蛋白依赖性激酶（CDK；如CDK1、CDK2、CDK4、CDK6和CDK7）及其唯一的伴侣细胞周期蛋白（如细胞周期蛋白A1、B1、D1 - 3和E1）驱动的。另一方面，这些阶段受到内源性CDK抑制剂如p16、p18、p19、p21和p27的负调控。此外，几个检查点控制细胞复制DNA和进行有丝分裂的进程，从而避免将基因组错误传递给子细胞。由于细胞周期相关基因的遗传和表观遗传异常，CDK在癌症中常常被组成性激活，其特征是转化细胞的不受控制的增殖。此外，一些癌基因和有缺陷的肿瘤抑制因子通过刺激细胞周期进入和进程或破坏DNA损伤反应（包括细胞周期检查点、DNA修复机制和细胞凋亡）来促进恶性变化。因此，与细胞周期调控相关的基因或蛋白质仍然是包括血液系统恶性肿瘤在内的各种癌症类型治疗中主要的关注靶点。在这种背景下，对细胞周期调控机制理解的进展为开发新的治疗方法提供了基础。本文总结了调控细胞周期的途径及其遗传和表观遗传改变；此外，还讨论了与细胞周期相关的各种已批准或潜在的治疗靶点，重点是血液系统恶性肿瘤。
