sGC-cGMP Signaling: Target for Anticancer Therapy
sGC-cGMP Signaling: Target for Anticancer Therapy
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DOI：
10.1007/978-1-4939-1031-1_2
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发表时间：
2014-01-01
期刊：
影响因子：
--
通讯作者：
Murad, Ferid
中科院分区：
文献类型：
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作者：
Bian, Ka;Murad, Ferid
在20世纪60年代报道了cGMP的生物内源性产生，随后证明了鸟苷酸环化酶活性以及可溶性和膜结合的鸟苷酸环化酶的同种型。在同一时期，cGMP特异性磷酸二酯酶也被发现。Murad的实验室建立了血管系统中内皮衍生松弛因子（EDRF）和cGMP浓度升高之间的联系。1998年10月12日，诺贝尔大会将诺贝尔医学奖或生理学奖授予科学家罗伯特·弗希戈特、路易斯·穆拉罗和费里德·穆拉德，以表彰他们在一氧化氮（NO）作为心血管系统信号分子方面的发现。与酶促合成NO的研究历史较短相比，1997年，含硝酸盐化合物被引入医药用途，标志着其150周年。甘油三硝酸酯（硝酸甘油; GTN）是这类化合物中的第一种。阿尔弗雷德·诺贝尔（诺贝尔奖的创始人）自己也患有心绞痛，医生给他开了硝酸甘油来治疗胸痛，而他却因为头痛而拒绝服用。在其首次化学用途后的近世纪，对一氧化氮和3 '，5'-环鸟苷一磷酸（NO/cGMP）途径的研究急剧扩展，并且NO/cGMP在生理学和病理学中的作用已被广泛研究。可溶性鸟苷酸环化酶（sGC）是NO的受体。α 1 β 1异二聚体是sGC的主要同种型，其对于催化活性是必需的。NO与β 1亚基组氨酸105处的亚铁（Fe 2+）血红素结合，导致sGC活性和cGMP产生增加至少200倍。本章综述了sGC-cGMP信号通路在细胞增殖中的研究进展，介绍了我们在肿瘤治疗中的靶向研究工作，并探讨了sGC-cGMP信号通路在染色质微环境中的作用。
The biologic endogenous production of cGMP was reported in the 1960s and followed by the demonstration of guanylyl cyclase activity and the isoforms of soluble and membrane-bound guanylyl cyclases. During the same period, cGMP specific phosphodiesterases also was discovered. Murad's lab established link between the endothelium derived relaxation factor (EDRF) and elevated cGMP concentration in the vascular system. October 12, 1998, the Nobel Assembly awarded the Nobel Prize in Medicine or Physiology to scientists Robert Furchgott, Louis Ignarro, and Ferid Murad for their discoveries concerning nitric oxide (NO) as a signaling molecule in the cardiovascular system. In contrast with the short research history of the enzymatic synthesis of NO, the introduction of nitrate-containing compounds for medicinal purposes marked its 150th anniversary in 1997. Glyceryl trinitrate (nitroglycerin; GTN) is the first compound of this category. Alfred Nobel (the founder of the Nobel Prize) himself had suffered from angina pectoris and was prescribed nitroglycerin for his chest pain while he refused to take due to the induction of headaches. Almost a century after its first chemical use, research in the nitric oxide and 3',5'-cyclic guanosine monophosphate (NO/cGMP) pathway has dramatically expanded and the role of NO/cGMP in physiology and pathology has been extensively studied. Soluble guanylyl cyclase (sGC) is the receptor for NO. The alpha 1 beta 1 heterodimer is the predominant isoform of sGC that is obligatory for catalytic activity. NO binds to the ferrous (Fe2+) heme at histidine 105 of the beta 1 subunit and leads to an increase in sGC activity and cGMP production of at least 200-fold. In this chapter, we reviewed the studies of sGC-cGMP signaling in cell proliferation; introduced our work of targeting sGC-cGMP signaling for cancer therapy; and explored the role of sGC-cGMP signaling in the chromatin-microenvironment.