Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.
Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation.
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DOI：
10.1016/j.ydbio.2005.11.009
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发表时间：
2006-02
影响因子：
2.7
通讯作者：
Xi‐De Wang;C. Leow;J. Zha;Zhijun Tang;Z. Modrušan;F. Radtke;M. Aguet;F. D. de Sauvage;Wei-qiang Gao
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文献类型：
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作者：
Xi‐De Wang;C. Leow;J. Zha;Zhijun Tang;Z. Modrušan;F. Radtke;M. Aguet;F. D. de Sauvage;Wei-qiang Gao
Notch信号通路对干/祖细胞在多种组织中的维持、生长和分化至关重要。使用转基因细胞消融方法，我们在之前的研究中发现，表达Notch 1的细胞对前列腺早期发育和再生长至关重要。在这里，我们进一步定义的作用Notch信号在调节前列腺上皮细胞的生长和分化，使用生物化学和遗传学方法在体外或体内系统。用Notch裂解和激活所需的γ-分泌酶/早老素抑制剂处理培养中生长的发育中的前列腺，引起共表达细胞角蛋白8和14的上皮细胞增殖的稳健增加，缺乏腔/基底层分离，并显著减少分支形态发生。使用条件性Notch 1基因缺失小鼠模型，我们发现Notch 1信号传导的失活会导致前列腺发生深刻的变化，包括簇状突起增加、桥接和上皮增殖增强。这些病变内的细胞共同表达管腔和基底细胞标志物，前列腺上皮细胞在分化前发育阶段的一个特点。微阵列分析显示，前列腺中Notch 1基因缺失后，许多遗传网络中的基因表达发生了改变。此外，Notch 1及其效应基因Hey-1在人前列腺癌中的表达与正常对照组织相比显著下调。总之，这些数据表明，Notch信号传导对前列腺中的正常细胞增殖和分化至关重要，并且该途径的失调可能促进前列腺肿瘤发生。
Notch pathway is crucial for stem/progenitor cell maintenance, growth and differentiation in a variety of tissues. Using a transgenic cell ablation approach, we found in our previous study that cells expressing Notch1 are crucial for prostate early development and re-growth. Here, we further define the role of Notch signaling in regulating prostatic epithelial cell growth and differentiation using biochemical and genetic approaches in ex vivo or in vivo systems. Treatment of developing prostate grown in culture with inhibitors of gamma-secretase/presenilin, which is required for Notch cleavage and activation, caused a robust increase in proliferation of epithelial cells co-expressing cytokeratin 8 and 14, lack of luminal/basal layer segregation and dramatically reduced branching morphogenesis. Using conditional Notch1 gene deletion mouse models, we found that inactivation of Notch1 signaling resulted in profound prostatic alterations, including increased tufting, bridging and enhanced epithelial proliferation. Cells within these lesions co-expressed both luminal and basal cell markers, a feature of prostatic epithelial cells in predifferentiation developmental stages. Microarray analysis revealed that the gene expression in a number of genetic networks was altered following Notch1 gene deletion in prostate. Furthermore, expression of Notch1 and its effector Hey-1 gene in human prostate adenocarcinomas were found significantly down-regulated compared to normal control tissues. Taken together, these data suggest that Notch signaling is critical for normal cell proliferation and differentiation in the prostate, and deregulation of this pathway may facilitate prostatic tumorigenesis.