title: GGPPS, a new EGR-1 target gene, reactivates ERK 1/2 signaling through increasing Ras prenylation.
abstract: 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.
authors: MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center and the Medical School of Nanjing University, National Resource Center for Mutant Mice, Nanjing, China.
authors: Ning
authors: N
authors: Shen
authors: Yue
authors: Y
authors: Shao
authors: Shan-Shan
authors: SS
authors: Lai
authors: Long
authors: L
authors: Qiao
authors: Run-Lin
authors: RL
authors: Yang
authors: Bin
authors: B
authors: Xue
authors: Fei-Yan
authors: FY
authors: Pan
authors: Hua-Qun
authors: HQ
authors: Chen
authors: Chao-Jun
authors: CJ
authors: Li
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000502:physiology; D051231:Farnesyltranstransferase / Q000235:genetics*; D025461:Feedback, Physiological; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D011014:Pneumonia / Q000209:etiology; D054876:Prenylation / Q000235:genetics*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012906:Smoke; D012907:Smoking / Q000009:adverse effects / Q000235:genetics*; D014158:Transcription, Genetic; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D034741:RNA, Small Interfering; D012906:Smoke; D051231:Farnesyltranstransferase; D018631:ras Proteins