Höpker K, Reinhardt H C
Klinik II für Innere Medizin, Uniklinik Köln.
Dtsch Med Wochenschr. 2013 Jan;138(3):82-6. doi: 10.1055/s-0032-1327380. Epub 2013 Jan 8.
The tumor suppressor p53 acts as a transcription factor downstream of many different stress-induced signaling pathways. Two major groups of p53-controlled genes can be distinguished. Those that mediate the initiation and maintenance of cell cycle checkpoints, and those driving apoptosis. An important determinant of the cellular reaction to DNA damage is the degree of genotoxic stress. The type of cellular response, which ranges from cell cycle arrest to apoptosis depends to a large extend on the severity of the genotoxic lesion. It remains largely unclear which molecular mechanisms govern the cellular decision between p53-driven cell cycle arrest and apoptosis. From a therapeutic perspective, this cellular decision is of utmost importance, as p53-driven apoptosis is therapeutically desired, when treating a malignant disease with DNA-damaging chemotherapy. However, a p53-driven cell cycle arrest might promote chemotherapy resistance, as it allows the tumor cells time to repair genotoxic lesions prior to the next cell division. Here, we summarize recent advances in our understanding of the molecular mechanisms controlling the functional outcome of p53 signaling. We further provide an outlook on the potential development of pharmacological interventions targeting the p53-regulating machinery to promote p53-driven apoptosis, while repressing p53-dependent cell cycle checkpoints.
肿瘤抑制因子p53作为许多不同应激诱导信号通路下游的转录因子发挥作用。可区分出两大类受p53调控的基因。一类介导细胞周期检查点的启动和维持，另一类驱动细胞凋亡。细胞对DNA损伤反应的一个重要决定因素是基因毒性应激的程度。细胞反应类型从细胞周期停滞到细胞凋亡，在很大程度上取决于基因毒性损伤的严重程度。目前仍不清楚哪些分子机制决定了细胞在p53驱动的细胞周期停滞和细胞凋亡之间的抉择。从治疗角度来看，这种细胞抉择至关重要，因为在用DNA损伤化疗治疗恶性疾病时，p53驱动的细胞凋亡是治疗所期望的。然而，p53驱动的细胞周期停滞可能会促进化疗耐药性，因为它使肿瘤细胞有时间在下一次细胞分裂前修复基因毒性损伤。在此，我们总结了我们对控制p53信号功能结果的分子机制理解的最新进展。我们还进一步展望了针对p53调节机制的药理学干预措施的潜在发展，以促进p53驱动的细胞凋亡，同时抑制p53依赖性细胞周期检查点。
