TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of human surfactant protein-A2 promoter activity

Dongyuan Liu, Ming Yi, Margaret Smith, Carole R. Mendelson

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Expression of the human surfactant protein-A2 (hSP-A2) gene is lung specific, occurs in type II and Clara cells, and is developmentally and hormonally regulated in fetal lung. Using transfected human fetal type II cells, we previously observed that ∼300 bp of 5′-flanking DNA mediated cAMP and interleukin-1 (IL-1) stimulation and dexamethasone (Dex) inhibition of hSP-A2 promoter activity. This region contains response elements for estrogen-related receptor α element (ERRE, -241 bp), thyroid transcription factor (TTF)-1/Nkx2.1 (TTF-binding protein, -171 bp), upstream stimulatory factor 1/2 (E-box, -80 bp), and stimulatory protein (Sp) 1 (G/T-box, -62 bp), which are essential for basal and cAMP induction of hSP-A2 expression. To define genomic regions necessary for developmental, hormonal, and tissue-specific regulation of hSP-A2 expression in vivo, we analyzed transgenic mice carrying hGH reporter genes comprised of 313 bp of hSP-A2 gene 5′-flanking DNA ± mutation in the TBE or 175 bp of 5′-flanking DNA, containing TBE, E-box and G/T-box, but lacking ERRE. Transgenes containing 313 or 175 bp of hSP-A2 5′-flanking DNA were expressed in a lung cell-specific manner and developmentally regulated in concert with the endogenous mouse SP-A gene. In cultured lung explants from hSP-A-313:hGH transgenic fetal mice, cAMP and IL-1 induced and Dex inhibited transgene expression. However, the 175-bp hSP-A2 genomic region was insufficient to mediate hormonal regulation of hSP-A2 promoter activity. The finding that expression of the hSP-A -313TBEmut:hGH transgene was essentially undetectable in fetal lung and was not hormonally regulated in transgenic fetal lung explants underscores the critical importance of the TBE in lung cell-specific, developmental, and hormonal regulation of hSP-A2 gene expression.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume295
Issue number2
DOIs
StatePublished - Aug 2008

Fingerprint

Response Elements
varespladib methyl
Surface-Active Agents
Lung
Proteins
Transgenes
DNA
Interleukin-1
Dexamethasone
Transgenic Mice
Upstream Stimulatory Factors
thyroid nuclear factor 1
Reporter Genes
Estrogen Receptors
Carrier Proteins
Thyroid Gland
Transcription Factors
Gene Expression
Mutation

Keywords

  • Adenosine 3′,5′-cyclic monophosphate
  • Fetal lung
  • Glucocorticoid
  • Tissue specific
  • Type II cell

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

@article{d873cf8497124cf6935a123076459722,
title = "TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of human surfactant protein-A2 promoter activity",
abstract = "Expression of the human surfactant protein-A2 (hSP-A2) gene is lung specific, occurs in type II and Clara cells, and is developmentally and hormonally regulated in fetal lung. Using transfected human fetal type II cells, we previously observed that ∼300 bp of 5′-flanking DNA mediated cAMP and interleukin-1 (IL-1) stimulation and dexamethasone (Dex) inhibition of hSP-A2 promoter activity. This region contains response elements for estrogen-related receptor α element (ERRE, -241 bp), thyroid transcription factor (TTF)-1/Nkx2.1 (TTF-binding protein, -171 bp), upstream stimulatory factor 1/2 (E-box, -80 bp), and stimulatory protein (Sp) 1 (G/T-box, -62 bp), which are essential for basal and cAMP induction of hSP-A2 expression. To define genomic regions necessary for developmental, hormonal, and tissue-specific regulation of hSP-A2 expression in vivo, we analyzed transgenic mice carrying hGH reporter genes comprised of 313 bp of hSP-A2 gene 5′-flanking DNA ± mutation in the TBE or 175 bp of 5′-flanking DNA, containing TBE, E-box and G/T-box, but lacking ERRE. Transgenes containing 313 or 175 bp of hSP-A2 5′-flanking DNA were expressed in a lung cell-specific manner and developmentally regulated in concert with the endogenous mouse SP-A gene. In cultured lung explants from hSP-A-313:hGH transgenic fetal mice, cAMP and IL-1 induced and Dex inhibited transgene expression. However, the 175-bp hSP-A2 genomic region was insufficient to mediate hormonal regulation of hSP-A2 promoter activity. The finding that expression of the hSP-A -313TBEmut:hGH transgene was essentially undetectable in fetal lung and was not hormonally regulated in transgenic fetal lung explants underscores the critical importance of the TBE in lung cell-specific, developmental, and hormonal regulation of hSP-A2 gene expression.",
keywords = "Adenosine 3′,5′-cyclic monophosphate, Fetal lung, Glucocorticoid, Tissue specific, Type II cell",
author = "Dongyuan Liu and Ming Yi and Margaret Smith and Mendelson, {Carole R.}",
year = "2008",
month = "8",
doi = "10.1152/ajplung.00069.2008",
language = "English (US)",
volume = "295",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "2",

}

TY - JOUR

T1 - TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of human surfactant protein-A2 promoter activity

AU - Liu, Dongyuan

AU - Yi, Ming

AU - Smith, Margaret

AU - Mendelson, Carole R.

PY - 2008/8

Y1 - 2008/8

N2 - Expression of the human surfactant protein-A2 (hSP-A2) gene is lung specific, occurs in type II and Clara cells, and is developmentally and hormonally regulated in fetal lung. Using transfected human fetal type II cells, we previously observed that ∼300 bp of 5′-flanking DNA mediated cAMP and interleukin-1 (IL-1) stimulation and dexamethasone (Dex) inhibition of hSP-A2 promoter activity. This region contains response elements for estrogen-related receptor α element (ERRE, -241 bp), thyroid transcription factor (TTF)-1/Nkx2.1 (TTF-binding protein, -171 bp), upstream stimulatory factor 1/2 (E-box, -80 bp), and stimulatory protein (Sp) 1 (G/T-box, -62 bp), which are essential for basal and cAMP induction of hSP-A2 expression. To define genomic regions necessary for developmental, hormonal, and tissue-specific regulation of hSP-A2 expression in vivo, we analyzed transgenic mice carrying hGH reporter genes comprised of 313 bp of hSP-A2 gene 5′-flanking DNA ± mutation in the TBE or 175 bp of 5′-flanking DNA, containing TBE, E-box and G/T-box, but lacking ERRE. Transgenes containing 313 or 175 bp of hSP-A2 5′-flanking DNA were expressed in a lung cell-specific manner and developmentally regulated in concert with the endogenous mouse SP-A gene. In cultured lung explants from hSP-A-313:hGH transgenic fetal mice, cAMP and IL-1 induced and Dex inhibited transgene expression. However, the 175-bp hSP-A2 genomic region was insufficient to mediate hormonal regulation of hSP-A2 promoter activity. The finding that expression of the hSP-A -313TBEmut:hGH transgene was essentially undetectable in fetal lung and was not hormonally regulated in transgenic fetal lung explants underscores the critical importance of the TBE in lung cell-specific, developmental, and hormonal regulation of hSP-A2 gene expression.

AB - Expression of the human surfactant protein-A2 (hSP-A2) gene is lung specific, occurs in type II and Clara cells, and is developmentally and hormonally regulated in fetal lung. Using transfected human fetal type II cells, we previously observed that ∼300 bp of 5′-flanking DNA mediated cAMP and interleukin-1 (IL-1) stimulation and dexamethasone (Dex) inhibition of hSP-A2 promoter activity. This region contains response elements for estrogen-related receptor α element (ERRE, -241 bp), thyroid transcription factor (TTF)-1/Nkx2.1 (TTF-binding protein, -171 bp), upstream stimulatory factor 1/2 (E-box, -80 bp), and stimulatory protein (Sp) 1 (G/T-box, -62 bp), which are essential for basal and cAMP induction of hSP-A2 expression. To define genomic regions necessary for developmental, hormonal, and tissue-specific regulation of hSP-A2 expression in vivo, we analyzed transgenic mice carrying hGH reporter genes comprised of 313 bp of hSP-A2 gene 5′-flanking DNA ± mutation in the TBE or 175 bp of 5′-flanking DNA, containing TBE, E-box and G/T-box, but lacking ERRE. Transgenes containing 313 or 175 bp of hSP-A2 5′-flanking DNA were expressed in a lung cell-specific manner and developmentally regulated in concert with the endogenous mouse SP-A gene. In cultured lung explants from hSP-A-313:hGH transgenic fetal mice, cAMP and IL-1 induced and Dex inhibited transgene expression. However, the 175-bp hSP-A2 genomic region was insufficient to mediate hormonal regulation of hSP-A2 promoter activity. The finding that expression of the hSP-A -313TBEmut:hGH transgene was essentially undetectable in fetal lung and was not hormonally regulated in transgenic fetal lung explants underscores the critical importance of the TBE in lung cell-specific, developmental, and hormonal regulation of hSP-A2 gene expression.

KW - Adenosine 3′,5′-cyclic monophosphate

KW - Fetal lung

KW - Glucocorticoid

KW - Tissue specific

KW - Type II cell

UR - http://www.scopus.com/inward/record.url?scp=52149118463&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52149118463&partnerID=8YFLogxK

U2 - 10.1152/ajplung.00069.2008

DO - 10.1152/ajplung.00069.2008

M3 - Article

C2 - 18487360

AN - SCOPUS:52149118463

VL - 295

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 2

ER -