The p75NTR mediates a bifurcated signal transduction cascade through the NF kappa B and JNK pathways to inhibit cell survival.
The p75NTR mediates a bifurcated signal transduction cascade through the NF kappa B and JNK pathways to inhibit cell survival.
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DOI：
10.1016/j.yexcr.2004.10.020
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发表时间：
2005-03
影响因子：
3.7
通讯作者：
Jeffrey A. Allen;Fatima S. Khwaja;S. Byers;D. Djakiew
中科院分区：
文献类型：
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作者：
Jeffrey A. Allen;Fatima S. Khwaja;S. Byers;D. Djakiew
p75NTR在神经系统中表达最丰富，但也广泛表达于许多其他器官和组织中，在这些器官和组织中，它主要作为细胞存活的负调节因子发挥作用。在前列腺中，p75NTR作为抑制性蛋白能够减缓增殖和诱导凋亡。已经表明，p75NTR在正常前列腺中表达，在体内从恶性肿瘤细胞中逐渐丢失，并且在源自转移的前列腺癌细胞系中基本上不存在。虽然p75NTR在前列腺癌中的作用已经被很好地确定，但介导其抑制活性的信号转导途径仅被部分阐明。这项研究表明，外源性表达的p75 NTR下调，以剂量依赖性的方式，分叉的信号级联反应，导致有效的转录效应的表达减少。通过使用p75 NTR的显性负性缺失构建体将这种双臂信号转导级联直接连接到上游受体，所述构建体将肿瘤细胞从p75 NTR诱导的存活丧失和促进凋亡中拯救出来。此外，显性负性挽救了信号转导中间体水平的改变。相反，使用受体下游的激酶失活中间体进一步降低了相关转录效应子的表达，并降低了细胞的存活率。这些结果提供了近端p75 NTR和导致转录效应因子NFκB和JNK的信号转导中间体之间的明确联系，以及相关的生长抑制和凋亡诱导。
p75NTRis most abundantly expressed in the nervous system, but is also widely expressed in many other organs and tissues where it primarily functions as a negative regulator of cell survival. In the prostate, p75NTRfunctions as an inhibitory protein capable of slowing proliferation and inducing apoptosis. It has been shown that p75NTRis expressed in the normal prostate, progressively lost from malignant tumor cells in vivo, and largely absent from prostate cancer cell lines derived from metastases. Although the role of p75NTRin prostate cancer has been well established, the signal transduction pathway that mediates its inhibitory activity has only been partially elucidated. This study demonstrates that exogenous expression of p75NTRdown-regulates, in a dose-dependent manner, a bifurcated signaling cascade that results in reduced expression of potent transcription effectors. This two-arm signal transduction cascade was directly linked to the upstream receptor by using dominant-negative deletion constructs of p75NTRthat rescued tumor cells from p75NTR-induced loss of survival and promotion of apoptosis. Furthermore, the dominant negatives rescued alterations in the levels of signal transduction intermediates. Conversely, the use of kinase-inactive intermediates that are downstream of the receptor further reduced expression of involved transcription effectors and reduced survival of the cells. These results provide a definitive link between the proximate p75NTRand signal transduction intermediates leading to the transcription effectors NFκB and JNK, with associated growth suppression and induction of apoptosis.