Wolter Sabine, Dittmar Fanni, Seifert Roland
Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Handb Exp Pharmacol. 2017;238:25-47. doi: 10.1007/164_2016_5007.
The cyclic nucleotides cAMP and cGMP are well-characterized second messenger molecules regulating many important intracellular processes, such as differentiation, proliferation, and apoptosis. The latter is a highly regulated process of programmed cell death wherein several regulatory proteins, like those belonging to the Bcl-2 family, are involved. The initiation of apoptosis is regulated by three different pathways: the intrinsic or mitochondrial, the extrinsic, and the ER stress pathway. Recently, it has been published that the pyrimidine cyclic nucleotides cCMP and cUMP also function as second messenger molecules, and additionally have an effect on apoptosis signaling pathways. cCMP induced PKA-independent apoptosis via the intrinsic and ER-stress pathway in S49 mouse lymphoma cells, and cCMP as well as cUMP induced apoptosis in human HEL cells via the intrinsic pathway. However, in human K-562 cells, which are known to be multidrug-resistant, cCMP and cUMP had no effect. Summarized in this chapter are the initiation of apoptosis by cCMP and cUMP regarding the various apoptotic pathways, the enzymes involved in apoptosis, as well as the most relevant methods for the detection and examination of apoptosis and the corresponding signaling pathways.
环核苷酸cAMP和cGMP是特征明确的第二信使分子，可调节许多重要的细胞内过程，如分化、增殖和凋亡。凋亡是一种高度受调控的程序性细胞死亡过程，涉及多种调控蛋白，如Bcl-2家族的蛋白。凋亡的起始由三种不同的途径调控：内源性或线粒体途径、外源性途径和内质网应激途径。最近有研究表明，嘧啶环核苷酸cCMP和cUMP也作为第二信使分子发挥作用，并且对凋亡信号通路有影响。cCMP通过内源性和内质网应激途径在S49小鼠淋巴瘤细胞中诱导非PKA依赖性凋亡，cCMP和cUMP通过内源性途径在人HEL细胞中诱导凋亡。然而，在已知具有多药耐药性的人K-562细胞中，cCMP和cUMP没有作用。本章总结了cCMP和cUMP在各种凋亡途径中引发凋亡的情况、凋亡相关的酶，以及检测和研究凋亡及相应信号通路的最相关方法。
