GPRC5A suppresses protein synthesis at the endoplasmic reticulum to prevent radiation-induced lung tumorigenesis.
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.
Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Jian
J
Wang
Department of Pathology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Alton B
AB
Farris
Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Kaiming
K
Xu
Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Ping
P
Wang
Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Xiangming
X
Zhang
Emory Integrated Proteomics Core and Biochemistry Department, Atlanta, Georgia 30322, USA.
Duc M
DM
Duong
Robert P. Apkaran Integrated Electron Microscope Core, Emory University, Atlanta, Georgia 30322, USA.
Hong
H
Yi
Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Hui-Kuo
HK
Shu
Department of Hemotology and Medical Oncology, Emory University School of Medicine and the Winship Cancer Institute, Atlanta, Georgia 30322, USA.
Shi-Yong
SY
Sun
Department of Radiation Oncology, Emory University School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA.
Ya
Y
Wang
D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D014176:Protein Biosynthesis; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D014158:Transcription, Genetic
D039562:Eukaryotic Initiation Factor-4F; C116760:GPRC5A protein, human; C554251:GPRC5A protein, mouse; D043562:Receptors, G-Protein-Coupled; C512478:EGFR protein, human; D066246:ErbB Receptors