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Estrogen-induced upregulation of Sftpb requires transcriptional control of neuregulin receptor ErbB4 in mouse lung type II epithelial cells.

ABSTRACT: Estrogen is known for its positive stimulatory effects on surfactant proteins. ErbB4 receptor and its ligand neuregulin (NRG) positively stimulate lung development. ErbB receptors interact with nuclear receptors and ErbB4 co-regulates estrogen receptor (ER)? expression in breast cells. ER? is highly expressed in pneumocytes and its deletion leads to fewer alveoli and reduced elastic recoil. A similar picture was seen in ErbB4-deleted lungs. We hypothesized that estrogen signals its effect on surfactant protein B (Sftpb) expression through interactions of ER? and ErbB4. Estrogen and NRG treatment decreased cell numbers and stimulated Sftpb expression in type II cells. Estrogen and NRG both stimulated phosphorylation of ER? and co-localization of both receptors. Overexpression of ER? increased the cell number and Sftpb expression, which was further augmented by estrogen and NRG. Finally, estrogen and NRG stimulated ER? and ErbB4 binding to the Sftpb promoter. Overexpression of these receptors stimulated Sftpb promoter activation, which was further enhanced by estrogen and NRG. The stimulatory effect of estrogen and NRG was abolished in ErbB4 deletion and reconstituted by re-expression of full-length ErbB4 in fetal ErbB4-deleted type II cells. Estrogen-induced nuclear translocation of ErbB4 required the intact ?-secretase cleavage site but not the nuclear localization sequence of the ErbB4 receptor, suggesting that ER? might function as a nuclear chaperone for ErbB4. These studies demonstrate that estrogen effects on Sftpb expression require an interaction of ER? and ErbB4. We speculate that the stimulatory effects of estrogen on Sftpb are under transcriptional control of ErbB4.

SUBMITTER: Zscheppang K

PROVIDER: S-EPMC3167574 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Estrogen-induced upregulation of Sftpb requires transcriptional control of neuregulin receptor ErbB4 in mouse lung type II epithelial cells.

Zscheppang Katja K Konrad Mirja M Zischka Melanie M Huhn Verena V Dammann Christiane E L CE

Biochimica et biophysica acta 20110708 10

Estrogen is known for its positive stimulatory effects on surfactant proteins. ErbB4 receptor and its ligand neuregulin (NRG) positively stimulate lung development. ErbB receptors interact with nuclear receptors and ErbB4 co-regulates estrogen receptor (ER)α expression in breast cells. ERβ is highly expressed in pneumocytes and its deletion leads to fewer alveoli and reduced elastic recoil. A similar picture was seen in ErbB4-deleted lungs. We hypothesized that estrogen signals its effect on sur ...[more]

PMID: 21777626

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Project description:BackgroundThe ketogenic diet (KD)has been considered an effective treatment for epilepsy, whereas its underlying mechanisms remain obscure. We have previously reported that the KD feeding increased Neuregulin 1 (NRG1) expression in the hippocampus; disruption of NRG1 signaling by genetically deleting its receptor-ErbB4 abolished KD's effects on inhibitory synaptic activity and seizures. However, it is still unclear about the mechanisms underlying the effect of KD on NRG1 expression and whether the effects of KD require ErbB4 kinase activity.MethodsThe effects of the KD on NRG1 expression were assessed via western blotting and real-time PCR. Acetylation level at the Nrg1 promoter locus was examined using the chromatin immunoprecipitation technique. Kainic acid (KA)-induced acute seizure model was utilized to examine the effects of KD and histone deacetylase inhibitor-TSA on seizures. Synaptic activities in the hippocampus were recorded with the technique of electrophysiology. The obligatory role of ErbB4 kinase activity in KD's effects on seizures and inhibitory synaptic activity was evaluated by using ErbB kinase antagonist and transgenic mouse-T796G.ResultsWe report that KD specifically increases Type I NRG1 expression in the hippocampus. Using the chromatin immunoprecipitation technique, we observe increased acetylated-histone occupancy at the Nrg1 promoter locus of KD-fed mice. Treatment of TSA dramatically elevates NRG1 expression and diminishes the difference between the effects of the control diet (CD) and KD. These data indicate that KD increases NRG1 expression via up-regulating histone acetylation. Moreover, both pharmacological and genetic inhibitions of ErbB4 kinase activity significantly block the KD's effects on inhibitory synaptic activity and seizure, suggesting an essential role of ErbB4 kinase activity.ConclusionThese results strengthen our understanding of the role of NRG1/ErbB4 signaling in KD and shed light on novel therapeutic interventions for epilepsy.

Dataset Information

Estrogen-induced upregulation of Sftpb requires transcriptional control of neuregulin receptor ErbB4 in mouse lung type II epithelial cells.

Publications

Estrogen-induced upregulation of Sftpb requires transcriptional control of neuregulin receptor ErbB4 in mouse lung type II epithelial cells.

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