Glucocorticoid inhibition of<i>SP-A</i>gene expression in lung type II cells is mediated via the TTF-1-binding element

Alcorn, Joseph L.; Islam, Kazi Nazrul; Young, Pampee P.; Mendelson, Carole R.

doi:10.1152/ajplung.00280.2003

Cited by 16 publications

(19 citation statements)

References 67 publications

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“…Previously, we observed that 378 bp of 5Ј-flanking DNA from the rabbit SP-A gene were sufficient to direct appropriate lung cell-specific and developmental regulation of expression in transgenic mice (4). In human fetal type II cell transfection studies using reporter constructs containing 5Ј-flanking sequences from the hSP-A2 gene, we observed that the TBE at Ϫ171 to Ϫ166 bp plays a critical role in cAMP, IL-1, and glucocorticoid regulation of hSP-A2 promoter activity (5,25,27,38). In the present study, we created transgenic mouse lines carrying hSP-A:hGH fusion genes comprised of 313 bp of hSP-A2 5Ј-flanking DNA, without and with a scramble mutation in the TBE (hSP-A Ϫ313TBEmut :hGH) and a fusion gene comprised of 175 bp of 5Ј-flanking sequence containing the core TBE, E-box, and G/T-box sequences, but lacking the ERRE.…”

Section: Hsp-a2 (175 Bp) 5ј-flanking Dna Is Sufficient For Lung Cell-mentioning

confidence: 79%

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TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of humansurfactant protein-A2promoter activity

Liu¹,

Yi²,

Smith³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Liu D, Yi M, Smith M, Mendelson CR. TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of human surfactant protein-A2 promoter activity. Am J Physiol Lung Cell Mol Physiol 295: L264 -L271, 2008. First published May 16, 2008 doi:10.1152/ajplung.00069.2008.-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 ϳ300 bp of 5Ј-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 ␣ element (ERRE, Ϫ241 bp), thyroid transcription factor (TTF)-1/Nkx2.1 (TTFbinding protein, Ϫ171 bp), upstream stimulatory factor 1/2 (E-box, Ϫ80 bp), and stimulatory protein (Sp) 1 (G/T-box, Ϫ62 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 5Ј-flanking DNA Ϯ mutation in the TBE or 175 bp of 5Ј-flanking DNA, containing TBE, E-box and G/T-box, but lacking ERRE. Transgenes containing 313 or 175 bp of hSP-A2 5Ј-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 Ϫ313: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-AϪ313TBEmut: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. fetal lung; tissue specific; type II cell; adenosine 3Ј,5Ј-cyclic monophosphate; glucocorticoid PULMONARY SURFACTANT, a developmentally regulated, phospholipid-rich lipoprotein required for air breathing, is synthesized exclusively by lung alveolar type II cells. To define the basic mechanisms involved in type II cell-specific, developmental, and hormonal regulation of surfactant synthesis, we have focused on surfactant protein (SP)-A, the major surfactant protein, that is an excellent marker of fetal lung maturity. Transcription of the SP-A gene is initiated in fetal lung after ϳ80% of gestation is completed and reaches maximal levels just before birth (44). Developmental regulation of SP-A gene expression in fetal lung is more closely associated with the induction of surfactant glycerophospholipid synthesis and appearance of identifiable type II cells than is the temporal regulation of genes encoding surfactant proteins...

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Section: Hsp-a2 (175 Bp) 5ј-flanking Dna Is Sufficient For Lung Cell-mentioning

confidence: 79%

“…SP-A expression in cultured human fetal lung explants and isolated type II cells is stimulated by hormones and factors that increase cAMP (2,51) and by interleukin-1 (IL-1) (25) and is inhibited by glucocorticoids, such as dexamethasone (Dex) (5,50,52). cAMP and IL-1 stimulation of SP-A expression is O 2 dependent (1,25,26).…”

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confidence: 99%

TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of humansurfactant protein-A2promoter activity

Liu¹,

Yi²,

Smith³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Expression of several genes is known to be affected by Dex-stimulation in various cell types, that is, NFKBIA (Alcorn et al, 2004;Chauhan et al, 2002;Medh et al, 2003), TNFAIP3 (Galon et al, 2002), RGS2 (Homme et al, 2003), and VDUP (Medh et al, 2003). All selected genes were significantly induced (Student's t test; p < .01) upon Dex-stimulation ( Figure 2C) in the control samples.…”

Section: Gene Expression In Peripheral Blood Samplesmentioning

confidence: 95%

Profiling Gene Expression in Whole Blood Samples Following an In-Vitro Challenge

Spijker¹,

Leemput

Hoekstra

et al. 2004

Twin Res

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“…SP-A expression by HFL epithelial cells is stimulated by cAMP and IL-1, which enhance recruitment to the hSP-A promoter of the critical transcription factors, thyroid transcription factor 1 (TTF-1/Nkx2.1) and nuclear factor B (NF-B), and histone-modifying cofactors, which promote permissive changes in chromatin structure (5,6). By contrast, cAMP induction of hSP-A expression is inhibited by glucocorticoids (7)(8)(9) and TGF-␤ (10,11) and is blocked by hypoxia (6,12). Notably, TGF-␤ mediates inhibitory effects of hypoxia on lung alveolar development in neonatal mice (13) and down-regulates TTF-1 expression in lung adenocarcinoma cells (14).…”

mentioning

confidence: 99%

The miR-200 Family and Its Targets Regulate Type II Cell Differentiation in Human Fetal Lung

Benlhabib

Guo

Pierce

et al. 2015

Journal of Biological Chemistry

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Background: SP-A, a type II cell differentiation marker, is stimulated by cAMP and inhibited by TGF-␤ in HFL. Results: cAMP enhances type II cell differentiation by repressing ZEB1 expression and TGF-␤ signaling. Conclusion: miR-200 targets, ZEB1/2 and TGF-␤2, inhibit type II cell differentiation by repressing TTF-1 transcriptional activity. Significance: This work presents the first evidence for roles of miR-200s and targets, ZEB1/2, in promoting type II differentiation and function.

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Glucocorticoid inhibition ofSP-Agene expression in lung type II cells is mediated via the TTF-1-binding element

Cited by 16 publications

References 67 publications

TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of humansurfactant protein-A2promoter activity

TTF-1 response element is critical for temporal and spatial regulation and necessary for hormonal regulation of humansurfactant protein-A2promoter activity

Profiling Gene Expression in Whole Blood Samples Following an In-Vitro Challenge

The miR-200 Family and Its Targets Regulate Type II Cell Differentiation in Human Fetal Lung

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