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PMID:17350185

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Citation

Zhu, NL, Li, C, Huang, HH, Sebald, M, Londhe, VA, Heisterkamp, N, Warburton, D, Bellusci, S and Minoo, P (2007) TNF-alpha represses transcription of human Bone Morphogenetic Protein-4 in lung epithelial cells. Gene 393:70-80

Abstract

Bone Morphogenetic Proteins are key signaling molecules in vertebrate development. Little is known about Bmp gene regulation in any organ. In Drosophila, the Bmp gene, dpp is regulated by Dorsal, the invertebrate homologue of Rel-NF-kB. In this study we examined whether TNF-alpha, which activates NF-kB, can regulate Bmp4 gene expression. TNF-alpha reduced Bmp4 mRNA in lung adenocarcinoma A549 cells and repressed transcriptional activity of the human Bmp4 promoter in a dose-dependent manner. Similar repression was observed when the Bmp4 promoter was co-transfected with a p65 (RelA) expression vector in the absence of TNF-alpha treatment, suggesting that RelA mediates the effect of TNF-alpha. In support of this finding, the repressor effect of TNF-alpha on Bmp4 was abrogated by a co-transfected dominant negative mutant of IkB (S32A/S36A). The human Bmp4 promoter contains 3 putative consensus binding sites for NF-kB. Surprisingly, only one of the latter binding sites was capable of binding NF-kB. Repressor effect of NF-kB was not dependent on any of the three binding sites, but localized to a 122 bp fragment which bound both RelA and SP1. SP1 stimulated transcription, whereas increasing doses of RelA opposed this effect. In vivo, TNF-alpha inhibited branching morphogenesis and LacZ gene expression in Bmp4-lacz transgenic lungs. These data support a model in which TNF-alpha-induced RelA interacts with SP1 to bring about transcriptional repression of Bmp4 gene. These findings provide a mechanistic paradigm for interactions between mediators of inflammation and morphogenesis with relevant implications for normal lung development and pathogenesis of disease.

Links

PubMed PMC1945170 Online version:10.1016/j.gene.2007.01.016

Keywords

Animals; Base Pairing/genetics; Base Sequence; Binding Sites; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins/genetics; Bone Morphogenetic Proteins/metabolism; Cell Line, Tumor; Enhancer Elements, Genetic/genetics; Epithelial Cells/drug effects; Epithelial Cells/metabolism; Gene Expression Regulation, Neoplastic/drug effects; Humans; Lung/cytology; Lung/drug effects; Lung/embryology; Lung/metabolism; Mice; Molecular Sequence Data; NF-kappa B/metabolism; Promoter Regions, Genetic/genetics; Protein Binding/drug effects; RNA, Messenger/genetics; RNA, Messenger/metabolism; Sequence Deletion; Transcription Factor RelA/metabolism; Transcription, Genetic/drug effects; Tumor Necrosis Factor-alpha/pharmacology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:TNFA

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TF65

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(NCBI_Gene:652)

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:TF65

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(NCBI_Gene:3569)

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:TF65

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0000976: transcription cis-regulatory region binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0061048: negative regulation of branching involved in lung morphogenesis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TNFA

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TF65

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TF65

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TF65

involved_in

GO:0045892: negative regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0044212: transcription regulatory region DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TF65

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:TF65

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(NCBI_Gene:652)

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:TF65

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000314: direct assay evidence used in manual assertion

F

occurs_at:(SO:0001952)

Seeded From UniProt

complete

HUMAN:TF65

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(NCBI_Gene:3569)

Seeded From UniProt

complete

MOUSE:BMP4

involved_in

GO:0061047: positive regulation of branching involved in lung morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

See also

References

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