Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Department of Pathology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Nat Commun. 2016 Jun 8;7:11795. doi: 10.1038/ncomms11795.
GPRC5A functions as a lung tumour suppressor to prevent spontaneous and environmentally induced lung carcinogenesis; however, the underlying mechanism remains unclear. Here we reveal that GPRC5A at the endoplasmic reticulum (ER) membrane suppresses synthesis of the secreted or membrane-bound proteins including a number of oncogenes, the most important one being Egfr. The ER-located GPRC5A disturbs the assembly of the eIF4F-mediated translation initiation complex on the mRNA cap through directly binding to the eIF4F complex with its two middle extracellular loops. Particularly, suppression of EGFR by GPRC5A contributes significantly to preventing ionizing radiation (IR)-induced lung tumorigenesis. Thus, GPRC5A deletion enhances IR-promoted EGFR expression through an increased translation rate, thereby significantly increasing lung tumour incidence in Gprc5a(-/-) mice. Our findings indicate that under-expressed GPRC5A during lung tumorigenesis enhances any transcriptional stimulation through an active translational status, which can be used to control oncogene expression and potentially the resulting related disease.
GPRC5A 作为一种肺肿瘤抑制因子，可防止自发性和环境诱导的肺癌发生；然而，其潜在的机制尚不清楚。在这里，我们揭示了内质网（ER）膜上的 GPRC5A 抑制了包括许多癌基因在内的分泌或膜结合蛋白的合成，其中最重要的是 Egfr。位于 ER 的 GPRC5A 通过其两个中间细胞外环直接与 eIF4F 复合物结合，干扰 mRNA 帽上由 eIF4F 介导的翻译起始复合物的组装。特别地，GPRC5A 对 EGFR 的抑制作用显著有助于防止电离辐射（IR）诱导的肺癌发生。因此，GPRC5A 的缺失通过增加翻译速率显著增强了 IR 促进的 EGFR 表达，从而使 Gprc5a(-/-) 小鼠的肺肿瘤发生率显著增加。我们的研究结果表明，在肺肿瘤发生过程中低表达的 GPRC5A 通过活跃的翻译状态增强了任何转录刺激，这可用于控制癌基因表达，并可能控制由此产生的相关疾病。
