Normal development and fertility of knockout mice lacking the tumor suppressor gene LRP1b suggest functional compensation by LRP1
Normal development and fertility of knockout mice lacking the tumor suppressor gene LRP1b suggest functional compensation by LRP1
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DOI：
10.1128/mcb.24.9.3782-3793.2004
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发表时间：
2004-05-01
影响因子：
5.3
通讯作者：
Herz, J
中科院分区：
文献类型：
--
作者：
Marschang, P;Brich, J;Herz, J
LRP1b和密切相关的LRP1是低密度脂蛋白受体家族的大成员。在蛋白水平上，LRP1b与LRP1相同55%，LRP1是一种多功能和发育必需的受体，在货物运输和细胞信号传导中发挥作用。体细胞LRP1b突变经常发生在非小细胞肺癌和尿路上皮癌中，表明其在细胞生长调节中起作用。与LRP1相反，lrp1b缺陷小鼠发育正常，很可能是由于其表达模式受限以及LRP1或其他受体的功能代偿。LRP1b主要在大脑中表达，在肾上腺和睾丸中存在差异剪接形式。尽管存在潜在的furin切割位点，与LRP1相反，LRP1b的免疫印迹显示存在单个600 kda的多肽物种。利用酵母双杂交方法，我们鉴定了两种细胞内蛋白，突触后密度蛋白95和芳烃受体相互作用蛋白，它们与LRP1b的细胞内结构域结合。此外，我们还发现了几种与细胞外结构域结合的潜在配体。对LRP1b敲除小鼠的分析可能为进一步了解LRP1b作为肿瘤抑制因子的作用和癌症发展机制提供帮助。
LRP1b and the closely related LRP1 are large members of the low-density lipoprotein receptor family. At the protein level LRP1b is 55% identical to LRP1, a multifunctional and developmentally essential receptor with roles in cargo transport and cellular signaling. Somatic LRP1b mutations frequently occur in non-small cell lung cancer and urothelial cancers, suggesting a role in the modulation of cellular growth. In contrast to LRP1, LRP1b-deficient mice develop normally, most likely due to its restricted expression pattern and functional compensation by LRP1 or other receptors. LRP1b is expressed predominantly in the brain, and a differentially spliced form is present in the adrenal gland and in the testis. Despite the presence of a potential furin cleavage site and in contrast to LRP1, immunoblotting for LRP1b reveals the presence of a single 600-kDa polypeptide species. Using a yeast two-hybrid approach, we have identified two intracellular proteins, the postsynaptic density protein 95 and the aryl hydrocarbon receptor-interacting protein, that bind to the intracellular domain of LRP1b. In addition, we have found several potential ligands that bind to the extracellular domain. Analysis of LRP1b knockout mice may provide further insights into the role of LRP1b as a tumor suppressor and into the mechanisms of cancer development.