DAP kinase - A proapoptotic gene that functions as a tumor suppressor
DAP kinase - A proapoptotic gene that functions as a tumor suppressor
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DOI：
10.1006/excr.2000.5134
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发表时间：
2001-03-10
影响因子：
3.7
通讯作者：
Kimchi, A
中科院分区：
文献类型：
--
作者：
Raveh, T;Kimchi, A
细胞凋亡对肿瘤的发生、发展和转移具有重要影响，已成为肿瘤领域的一个备受关注和研究的课题。在肿瘤发展的不同阶段，细胞会受到应激条件的影响，从而引发程序性细胞死亡，因此导致细胞凋亡抑制的突变赋予细胞选择性优势。在癌前细胞中，癌基因的激活和随之而来的过度增殖引起细胞反应，导致通过凋亡消除这些细胞。随后，肿瘤微环境中的转化细胞处于恒定的选择性压力下，例如缺氧（缺氧），生长/存活因子耗尽，免疫系统攻击，以及由于细胞-基质相互作用丧失而导致的失巢凋亡。在后期阶段，当转移的肿瘤细胞进入循环时，它们遇到许多额外的死亡诱导信号，如超氧化物、一氧化氮、杀伤细胞因子和机械剪切力。因此，沿着，肿瘤发生的多阶段过程诱导细胞凋亡作为肿瘤抑制机制发挥作用，并且细胞必须逃离各种细胞凋亡诱导剂以存活（综述于Kaufmann和Gores，2000; Lowe和Lin，2000; Wyllie等，1999年）。这意味着肿瘤细胞应该从突变中受益，这些突变要么破坏各种细胞内蛋白质，这些蛋白质正介导程序性细胞死亡，要么激活抗凋亡基因。第一个建立凋亡机制中的基因在癌症中突变的概念的例子是Bcl-2的克隆。该基因位于滤泡性B细胞淋巴瘤特征性的（8; 14）染色体易位位点的初步发现（Tsujimoto等，1984）之后是在转基因小鼠模型中进行的精细研究，这些研究共同确立了Bcl-2活化在促进细胞存活和体内淋巴瘤发生中的作用（McDonnell等人，1989; Strasser等人，1990年）。第二个公认的例子是p53基因，其促凋亡功能自从首次被记录以来就已经被彻底研究（Yonish-Rouach et al.，1991年）。p53的失活突变经常在广泛的人类肿瘤中发现。通过缺失或突变使p53失活，降低了细胞对癌基因激活、缺氧、端粒侵蚀、细胞粘附变化和DNA损伤剂引发的细胞凋亡的敏感性，从而在肿瘤发展的不同阶段提供了强有力的阳性选择（Gottlieb和Oren，1998中综述）。这两个经过充分研究的例子为建立细胞凋亡和癌症之间的联系提供了里程碑。鉴于细胞凋亡分子网络的复杂性和致瘤性多步骤过程中应激信号的多样性，寻找可能参与癌症发展的其他凋亡基因变得令人感兴趣。因此，当死亡相关蛋白（DAP）激酶首次在我们的实验室中被分离出来作为细胞凋亡的阳性介质时，最令人兴奋的问题之一就是要找出它是否可以作为肿瘤抑制基因发挥作用。本文就近年来从不同角度探讨DAP激酶与癌症之间可能联系的研究作一综述。
Having a major impact on tumor initiation, progression, and metastasis, apoptosis has become a subject that draws tremendous attention and research efforts in the cancer field. At various stages during tumor development, cells are subjected to stressful conditions that trigger programmed cell death, and thus mutations leading to inhibition of apoptosis confer a selective advantage to cells. In premalignant cells, activation of oncogenes and the consequent hyperproliferation provoke a cellular response that leads to elimination of those cells by apoptosis. Subsequently, transformed cells in the tumor microenvironment are under constant selective pressure, such as lack of oxygen (hypoxia), depletion of growth/survival factors, attacks by the immune system, and often death by anoikis due to loss of cell–matrix interactions. At later stages, when metastasizing tumor cells enter into circulation they encounter many additional death-inducing signals such as superoxides, nitric oxides, killing cytokines, and mechanical shearing forces. Thus, all along the multistage process of tumorigenesis induction of apoptosis functions as a tumor-suppressor mechanism and cells have to escape from various inducers of apoptosis in order to survive (reviewed in Kaufmann and Gores, 2000; Lowe and Lin, 2000; Wyllie et al., 1999). This means that tumor cells should benefit from mutations that either inactivate various intracellular proteins which positively mediate programmed cell death or activate antiapoptotic genes. The first example which established the concept that genes in the apoptotic machinery are mutated in cancer was documented with the cloning of Bcl-2. The initial findings that this gene resides at the site of (8; 14) chromosomal translocation characteristic of follicular B cell lymphoma (Tsujimoto et al., 1984) were followed by the elegant studies performed in transgenic mice models which altogether established a role for Bcl-2 activation in promoting cell survival and in vivo lymphomagenesis (McDonnell et al., 1989; Strasser et al., 1990). The second well-established example is the p53 gene whose proapoptotic functions have been thoroughly studied ever since they were first documented (Yonish-Rouach et al., 1991). Inactivating mutations of p53 are frequently found in a wide range of human tumors. The inactivation of p53, by deletions or mutations, reduces the sensitivity of cells to apoptosis triggered by oncogene activation, hypoxia, telomere erosion, changes in cell adhesion, and DNA-damaging agents, thus providing a powerful positive selection at the different stages of tumor development (reviewed in Gottlieb and Oren, 1998). These two well-studied examples provided the milestones for establishing the link between apoptosis and cancer. In light of the complexity of the molecular network of apoptosis and the diversity of stress signals operating in the multistep process of tumorigenicity, it became of interest to look for additional apoptotic genes which may be involved in cancer development. Therefore, when death-associated protein (DAP) kinase was first isolated in our laboratory as a positive mediator of apoptosis, one of the most exciting questions was to find out whether it may function as a tumor-suppressor gene. This article is devoted to recent studies which investigated from different angles the possible link between DAP kinase and cancer.