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.

Redox state influence on human galectin-1 function

“…As a molecular switch for regulating cellular signal transduction, Ras (including K-, N-and H-Ras) cycles between the GDPbound inactive form and the GTP-bound active form. All Ras proteins undergo the post-translational modification prenylation at a particular sequence motif on their C-terminus to enable normal function [17,18]. This prenylation of Ras proteins, specifically farnesylation (attachment of a 15-carbon farnesyl moiety) or geranylgeranylation (attachment of a 20-carbon geranylgeranyl moiety), is responsible for facilitating Ras anchorage within the cell membrane, a process that is vital for Ras biological activities.…”

Protein prenylation and human diseases: a balance of protein farnesylation and geranylgeranylation

“…In our previous study, cigarette smoke induced the early growth response gene (Egr-1) expression through MAPK signaling and regulated the metalloprotease activity and the inflammation in pulmonary [1921]. We revealed that Egr-1 could bind to the promoter of GGPPS gene in a cigarette smoke dependent way through ChIP and identified GGPPS as one of the target genes of Egr-1 [22]. Furthermore, both Egr-1 and its target genes GGPPS and HO-1 were increasingly expressed in the lung from the cigarette smoke induced COPD mice.…”

Gene knockouts that affect Sertoli cell function

“…FPP and GGPP prenylate proteins that have a CaaX motif in their carbon termini, such as the RAS superfamily of GTPases [62]. GGPP synthase 1 (GGPPS) is a member of the prenyltransferase family, and it catalyzes the synthesis GGPP from FPP [63]. Inactivation of GGPPS in Sertoli cells results in constitutive activation of the proinflammatory mitogen-activated protein kinases (MAPK) and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathways due to the enhanced farnesylation of H-Ras [43].…”