Schmitt Estelle, Paquet Claudie, Beauchemin Myriam, Bertrand Richard
Notre Dame Hospital and Montreal Cancer Institute, Research Centre of University of Montreal Hospital Centre, Montreal, QUE, Canada.
J Zhejiang Univ Sci B. 2007 Jun;8(6):377-97. doi: 10.1631/jzus.2007.B0377.
Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senescence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving "sensor" proteins that sense the damage, and transmit signals to "transducer" proteins, which, in turn, convey the signals to numerous "effector" proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.
组织稳态需要细胞增殖、细胞衰老和细胞死亡之间精心编排的平衡。细胞通过由细胞周期蛋白依赖性激酶活性严格调控的细胞周期进行增殖。细胞衰老是一种保护程序，可限制生物体中细胞的增殖能力。细胞凋亡通过调节和影响细胞死亡的基因产物的协同作用消除不需要的细胞。细胞周期、细胞衰老、凋亡调节、癌症发展和肿瘤对癌症治疗的反应之间的密切联系已变得极为明显。对肿瘤抑制基因、癌基因、细胞周期和凋亡调节基因的广泛研究揭示了被称为DNA损伤反应网络的DNA损伤感知和信号通路是如何与细胞增殖、细胞周期停滞、细胞衰老和凋亡相关联的。DNA损伤反应很复杂，涉及感知损伤的“传感器”蛋白，并将信号传递给“转导器”蛋白，而“转导器”蛋白又将信号传递给许多参与特定细胞通路的“效应器”蛋白，包括DNA修复机制、细胞周期检查点、细胞衰老和凋亡。Bcl-2蛋白家族是细胞凋亡最关键的调节因子之一，在决定细胞在癌症化疗和放疗后是存活还是死亡方面发挥着重要作用。此外，现在有几项研究表明，Bcl-2家族成员还与细胞周期、DNA修复/重组和细胞衰老相互作用，这些作用通常与其在细胞凋亡中的功能不同。在这篇综述中，我们报告了在理解DNA损伤后调节细胞周期检查点、细胞衰老和细胞凋亡的分子网络方面取得的进展，并讨论了一些Bcl-2家族成员对细胞周期检查点调节的影响。
