cAMP-responding element-binding protein and c-Ets1 interact in the regulation of ATP-dependent MUC5AC gene expression

Seob Song Kyoung, Tae Jin Lee, Kyubo Kim, Kwang Chul Chung, Joo Heon Yoon

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Exogenous ATP activates purinoreceptors on the cell surface that regulate diverse cellular functions, including mucous cell secretion in the respiratory epithelium. In this study, ATP increased MUC5AC mRNA in primary human nasal epithelial cells and in NCI-H292 pulmonary adenocarcinoma cells in vitro. ATP-induced MUC5AC mRNA was mediated by phospholipase Cβ3. A dominant-negative mutation in the PDZ binding domain of PLCβ3 inhibited ATP-induced MUC5AC gene expression. ATP sequentially activated the phosphorylation of Akt, ERK1/2, p38, RSK1, and cAMP-responding element-binding protein (CREB) in a protein kinase C-independent manner. ATP-induced MUC5AC mRNA levels were regulated by CREB via direct interaction with c-Ets1 on the MUC5AC gene promoter (located -938 to -930). Effects of CREB and c-Ets1 were additive. Inhibition of either CREB or c-Ets1 inhibited ATP-induced MUC5AC gene expression. Stimulation with ATP caused the direct binding of CREB and c-Ets1 to the MUC5AC promoter, increasing the phosphorylation of c-Ets1. Chromatin immunoprecipitation assays demonstrated that in the presence of ATP, both c-Ets1 and CREB bound to the MUC5AC promoter. The effects of exogenous ATP on MUC5AC gene expression are mediated by a complex regulatory cascade controlling interactions between CREB and c-Ets1 that bind to a promoter element in the MUC5AC gene enhancing MUC5AC gene transcription. ATP-dependent activation of MUC5AC gene expression via CREB-c-Ets1 may contribute to mucous cell hypersecretion associated with common respiratory disorders.

Original languageEnglish
Pages (from-to)26869-26878
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number40
DOIs
Publication statusPublished - 2008 Oct 3

Fingerprint

Gene expression
Carrier Proteins
Adenosine Triphosphate
Gene Expression
Phosphorylation
Genes
Messenger RNA
PDZ Domains
Respiratory Mucosa
Phospholipases
Chromatin Immunoprecipitation
Transcription
Nose
Protein Kinase C
Chromatin
Assays
Epithelial Cells
Chemical activation
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Kyoung, Seob Song ; Lee, Tae Jin ; Kim, Kyubo ; Chung, Kwang Chul ; Yoon, Joo Heon. / cAMP-responding element-binding protein and c-Ets1 interact in the regulation of ATP-dependent MUC5AC gene expression. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 40. pp. 26869-26878.
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abstract = "Exogenous ATP activates purinoreceptors on the cell surface that regulate diverse cellular functions, including mucous cell secretion in the respiratory epithelium. In this study, ATP increased MUC5AC mRNA in primary human nasal epithelial cells and in NCI-H292 pulmonary adenocarcinoma cells in vitro. ATP-induced MUC5AC mRNA was mediated by phospholipase Cβ3. A dominant-negative mutation in the PDZ binding domain of PLCβ3 inhibited ATP-induced MUC5AC gene expression. ATP sequentially activated the phosphorylation of Akt, ERK1/2, p38, RSK1, and cAMP-responding element-binding protein (CREB) in a protein kinase C-independent manner. ATP-induced MUC5AC mRNA levels were regulated by CREB via direct interaction with c-Ets1 on the MUC5AC gene promoter (located -938 to -930). Effects of CREB and c-Ets1 were additive. Inhibition of either CREB or c-Ets1 inhibited ATP-induced MUC5AC gene expression. Stimulation with ATP caused the direct binding of CREB and c-Ets1 to the MUC5AC promoter, increasing the phosphorylation of c-Ets1. Chromatin immunoprecipitation assays demonstrated that in the presence of ATP, both c-Ets1 and CREB bound to the MUC5AC promoter. The effects of exogenous ATP on MUC5AC gene expression are mediated by a complex regulatory cascade controlling interactions between CREB and c-Ets1 that bind to a promoter element in the MUC5AC gene enhancing MUC5AC gene transcription. ATP-dependent activation of MUC5AC gene expression via CREB-c-Ets1 may contribute to mucous cell hypersecretion associated with common respiratory disorders.",
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cAMP-responding element-binding protein and c-Ets1 interact in the regulation of ATP-dependent MUC5AC gene expression. / Kyoung, Seob Song; Lee, Tae Jin; Kim, Kyubo; Chung, Kwang Chul; Yoon, Joo Heon.

In: Journal of Biological Chemistry, Vol. 283, No. 40, 03.10.2008, p. 26869-26878.

Research output: Contribution to journalArticle

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AU - Lee, Tae Jin

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AU - Yoon, Joo Heon

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