Qu Xiangping, Xiao Dongmei, Weber H Christian
Section of Gastroenterology, Boston University School of Medicine, Boston, MA 02118, USA.
J Mol Neurosci. 2004;22(1-2):75-82. doi: 10.1385/JMN:22:1-2:75.
The mammalian gastrin-releasing peptide receptor (GRP-R) belongs to the superfamily of G protein-coupled receptors and mediates actions of the regulatory GRP and bombesin, the amphibian homolog of GRP. Owing to its frequent ectopic expression in some epithelial human malignancies, such as cancers of the colon, lung, and prostate, ligand-specific receptor activation may initiate intracellular signals of cell proliferation, differentiation and migration in this context. Because the underlying molecular mechanisms of aberrant human GRP-R (hGRP-R) expression in tumorigenesis remain unknown, we examined in this study the transcriptional activation of hGRP-R in gastrointestinal and prostate cancer cells, which natively express functional hGRP-R. Using various hGRP-R promoter mutants cloned into a luciferase reporter plasmid, transient transfection studies demonstrated robust transcriptional activation in gastrointestinal and prostate cancer cells. Although our study revealed distinct patterns of transcriptional hGRP-R activation in gastrointestinal and prostate cancer cells, genomic sequences between 97 and 247 bp upstream of the major RNA initiation site appear to be of particular significance for basal transcriptional hGRP-R activation. Based on this study, future examination of transcription factor interaction with the hGRP-R promoter will be important to identify molecular mechanisms of hGRP-R regulation relevant in human cancers that express functional receptor sites
哺乳动物胃泌素释放肽受体（GRP-R）属于G蛋白偶联受体超家族，介导调节性胃泌素释放肽（GRP）和铃蟾肽（GRP的两栖类同源物）的作用。由于其在某些人类上皮恶性肿瘤（如结肠癌、肺癌和前列腺癌）中频繁异位表达，在此情况下，配体特异性受体激活可能会引发细胞增殖、分化和迁移的细胞内信号。由于人类GRP-R（hGRP-R）在肿瘤发生过程中异常表达的潜在分子机制尚不清楚，我们在本研究中检测了天然表达功能性hGRP-R的胃肠道和前列腺癌细胞中hGRP-R的转录激活情况。使用克隆到荧光素酶报告质粒中的各种hGRP-R启动子突变体，瞬时转染研究表明在胃肠道和前列腺癌细胞中有强大的转录激活。尽管我们的研究揭示了胃肠道和前列腺癌细胞中hGRP-R转录激活的不同模式，但主要RNA起始位点上游97至247 bp之间的基因组序列似乎对hGRP-R的基础转录激活具有特别重要的意义。基于这项研究，未来研究转录因子与hGRP-R启动子的相互作用对于确定在表达功能性受体位点的人类癌症中与hGRP-R调节相关的分子机制将很重要。
