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Receptor for advanced glycation end products (RAGE) signaling induces CREB-dependent chromogranin expression during
Henri J Huttunen1, Juha Kuja-Panula, Heikki Rauvala
1Programme of Molecular Neurobiology, Institute of Biotechnology and the Department of Biosciences, University of Helsinki, Helsinki FIN-00014, Finland. Henri.Huttunen@helsinki.fi
Abstract:
Receptor for advanced glycation end products (RAGE) mediates neurite outgrowth and cell migration upon stimulation with its ligand, amphoterin. We show here that RAGE-dependent changes in cell morphology are associated with proliferation arrest and changes in gene expression in neuroblastoma cells. Chromogranin B, a component of secretory vesicles in endocrine cells and neurons, was found to be up-regulated by RAGE signaling during differentiation of neuroblastoma cells along with the two other members of the chromogranin family, chromogranin A and secretogranin II. Ligation of RAGE by amphoterin lead to rapid phosphorylation and nuclear localization of cyclic AMP response element-binding protein (CREB), a major regulator of chromogranin expression. Furthermore, inhibition of ERK1/2-Rsk2-dependent CREB phosphorylation efficiently inhibited up-regulation of chromogranin gene expression upon RAGE activation. To further study the effects of RAGE and amphoterin on cellular differentiation, we stimulated embryonic stem cells expressing RAGE or a signaling-deficient mutant of RAGE with amphoterin. Amphoterin was found to promote RAGE-dependent neuronal differentiation of embryonic stem cells characterized by up-regulation of neuronal markers light neurofilament protein and beta-III-tubulin, activation of CREB, and increased expression of chromogranins A and B. These data suggest that RAGE signaling is capable of driving neuronal differentiation involving CREB activation and induction of chromogranin expression.
Insights
Receptor for advanced glycation end products (RAGE) signaling, triggered by amphoterin, promotes neuronal differentiation. This process involves CREB activation and upregulates chromogranin expression in neuroblastoma and embryonic stem cells.
Area of Science:
- Neuroscience
- Cell Biology
- Molecular Biology
Background:
- Receptor for advanced glycation end products (RAGE) is known to mediate neurite outgrowth and cell migration.
- RAGE signaling influences cell morphology, proliferation, and gene expression in neuroblastoma cells.
Purpose of the Study:
- To investigate the role of RAGE signaling in neuroblastoma cell differentiation and gene expression.
- To explore the impact of RAGE and amphoterin on neuronal differentiation in embryonic stem cells.
Main Methods:
- Stimulation of neuroblastoma and embryonic stem cells with amphoterin.
- Analysis of RAGE-dependent changes in cell morphology, proliferation, and gene expression.
- Investigation of the involvement of cyclic AMP response element-binding protein (CREB) phosphorylation and ERK1/2-Rsk2 pathway.
Main Results:
- RAGE activation in neuroblastoma cells led to proliferation arrest and upregulation of chromogranins A, B, and secretogranin II.
- Amphoterin-induced RAGE ligation resulted in CREB phosphorylation and nuclear localization, crucial for chromogranin expression.
- Inhibition of CREB phosphorylation blocked RAGE-induced chromogranin gene upregulation.
- Amphoterin promoted RAGE-dependent neuronal differentiation in embryonic stem cells, marked by increased neuronal markers and chromogranin expression.
Conclusions:
- RAGE signaling, activated by amphoterin, drives neuronal differentiation.
- The process involves CREB activation and induction of chromogranin expression.
- RAGE plays a significant role in neurogenesis and cellular differentiation pathways.
