GGPPS, a New EGR-1 Target Gene, Reactivates ERK 1/2 Signaling through Increasing Ras Prenylation

• Published in: The American journal of pathology Vol. 179; no. 6; pp. 2740 - 2750
• Main Authors: Shen, Ning, Shao, Yue, Lai, Shan-Shan, Qiao, Long, Yang, Run-Lin, Xue, Bin, Pan, Fei-Yan, Chen, Hua-Qun, Li, Chao-Jun
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.12.2011; American Society for Investigative Pathology
• Subjects: Animals; Biological and medical sciences; Cells, Cultured; Early Growth Response Protein 1 - genetics; Early Growth Response Protein 1 - physiology; Farnesyltranstransferase - genetics; Feedback, Physiological; HEK293 Cells; Humans; Investigative techniques, diagnostic techniques (general aspects); MAP Kinase Signaling System - genetics; Medical sciences; Mice; Mice, Mutant Strains; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Pneumonia - etiology; Prenylation - genetics; ras Proteins - metabolism; Regular; RNA, Small Interfering - pharmacology; Smoke; Smoking - adverse effects; Smoking - genetics; Transcription, Genetic; Signal transduction; Anatomic pathology; Early Growth Response Transcription Factor 1; Targeting; Extracellular signal-regulated protein kinase; Enzyme; Transferases; C-Onc gene; Mitogen-activated protein kinase; Genetics; Ras gene; Protooncogene
• ISSN: 0002-9440; 1525-2191
• DOI: 10.1016/j.ajpath.2011.08.011

Cigarette smoke activates the extracellular signal-regulated kinase (ERK) 1/2 mitogen activated-protein kinase pathway, which, in turn, is responsible for early growth response gene-1 (EGR-1) activation. Here we provide evidence that EGR-1 activation can also reactivate ERK 1/2 mitogen activated-protein kinase through a positive feedback loop through its target gene (geranylgeranyl diphosphate synthase) GGPPS . For the first time, the GGPPS gene is identified as a target of EGR-1, as EGR-1 can directly bind to the predicted consensus-binding site in the GGPPS promoter and regulate its transcription. Long-term observations show that there are two ERK 1/2 phosphorylation peaks after cigarette smoke extract stimulation in human lung epithelial Beas-2B cells. The first peak (at 10 minutes) is responsible for EGR-1 accumulation, and the second (at 4 hours) is diminished after the disruption of EGR-1 transcriptional activity. EGR-1 overexpression enhances Ras prenylation and membrane association in a GGPPS-dependent manner, and it augments ERK 1/2 activation. Likewise, a great reduction of the second peak of ERK 1/2 phosphorylation is observed during long-term cigarette smoke extract stimulation in cells where GGPPS is disrupted. Thus, we have uncovered an intricate positive feedback loop in which ERK 1/2-activated EGR-1 promotes ERK 1/2 reactivation through promoting GGPPS transcription, which might affect cigarette smoke-related lung pathological processes.