NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor type that is typically metastatic upon diagnosis. We have a poor understanding of the factors that control SCLC progression and metastasis. TheNFIB transcription factor is frequently amplified in mouse models of SCLC, but clear evidence that NFIB promotes SCLC in vivo is lacking.

Mesenchymal nuclear factor I B regulates cell proliferation and epithelial differentiation during lung maturation.

The Nuclear factor I (NFI) transcription factor family consists of four genes (Nfia, Nfib, Nfic and Nfix) that regulate the development of multiple organ systems in mice and humans. Nfib is expressed in both lung mesenchyme and epithelium and mice lacking Nfib have severe lung maturation defects and die at birth. Here we continue our analysis of the phenotype of Nfib⁻/⁻ lungs and show that Nfib specifically in lung mesenchyme controls late epithelial and mesenchymal cell proliferation and differentiation.

Involvement of transcription factor NR2F2 in human trophoblast differentiation.

Background: During the in vitro differentiation of human villous cytotrophoblast (CTB) cells to a syncytiotrophoblast (STB) phenotype, mRNA levels for the nuclear hormone receptor NR2F2 (ARP-1, COUP-TFII) increase rapidly, reaching a peak at day 1 of differentiation that is 8.8-fold greater than that in undifferentiated CTB cells. To examine whether NR2F2 is involved in the regulation of villous CTB cell differentiation, studies were performed to determine whether NR2F2 regulates the expression of TFAP2A (AP-2alpha), a transcription factor that is critical for the terminal differentiation of these cells to a STB phenotype.

Surfactant-associated protein B is critical to survival in nickel-induced injury in mice.

The etiology of acute lung injury is complex and associated with numerous, chemically diverse precipitating factors. During acute lung injury in mice, one key event is epithelial cell injury that leads to reduced surfactant biosynthesis. We have previously reported that transgenic mice that express transforming growth factor alpha (TGFA) in the lung were protected during nickel-induced lung injury.

TEAD1 inhibits prolactin gene expression in cultured human uterine decidual cells.

Forced overexpression of TEAD1 in human uterine fibroblast (HUF) and human endometrial stromal cells markedly inhibited prolactin promoter activity in both cell types in a dose-dependent manner, with maximal inhibition of greater than 90%. Conversely, the knockdown of TEAD1 expression in HUF cells with a TEAD1 siRNA resulted in a 75-80% increase in prolactin mRNA levels (p<0.01) compared to control cells exposed to a scrambled nonsense RNA.

Toll-like receptors and agonist responses in the developing fetal sheep lung.

Toll-like receptors (TLRs) are pattern recognition molecules that initiate innate immune responses. Intra-amniotic exposure of fetal sheep to pro-inflammatory stimuli causes pulmonary inflammation and induced lung maturation. We examined TLR ontogeny and fetal lung responsiveness to three different TLR agonists.

Pulmonary and systemic induction of SAA3 after ventilation and endotoxin in preterm lambs.

Serum amyloid A (SAA), an acute phase reactant (APR) protein, is induced in liver during systemic inflammation. Serum amyloid A3 (SAA3), an isoform of SAA, is induced in both liver and extra hepatic sites in response to proinflammatory stimuli such as cytokines. Previously, we showed a modest increase in plasma cytokine levels in a preterm lamb model of lung injury.

The transcription factor gene Nfib is essential for both lung maturation and brain development.

The phylogenetically conserved nuclear factor I (NFI) gene family encodes site-specific transcription factors essential for the development of a number of organ systems. We showed previously that Nfia-deficient mice exhibit agenesis of the corpus callosum and other forebrain defects, whereas Nfic-deficient mice have agenesis of molar tooth roots and severe incisor defects. Here we show that Nfib-deficient mice possess unique defects in lung maturation and exhibit callosal agenesis and forebrain defects that are similar to, but more severe than, those seen in Nfia-deficient animals.

Vascular changes after intra-amniotic endotoxin in preterm lamb lungs.

Chorioamnionitis is associated with preterm delivery and bronchopulmonary dysplasia (BPD), characterized by impaired alveolar and pulmonary vascular development and vascular dysfunction. To study the vascular effects in a model of chorioamnionitis, preterm lambs were exposed to 20 mg of intra-amniotic endotoxin or saline for 1, 2, 4, or 7 days and delivered at 122 days gestational age (term = 150 days). This intra-amniotic endotoxin dose was previously shown to induce lung maturation.

Nuclear factor I/thyroid transcription factor 1 interactions modulate surfactant protein C transcription.

Surfactant protein C (SP-C; Sftpc) gene expression is restricted to pulmonary type II epithelial cells. The proximal SP-C promoter region contains critical binding sites for nuclear factor I (NFI) and thyroid transcription factor 1 (TTF-1; also called Nkx2.1).

TTF-1 phosphorylation is required for peripheral lung morphogenesis, perinatal survival, and tissue-specific gene expression.

Thyroid transcription factor-1 (TTF-1) is a 43-kDa, phosphorylated member of the Nkx2 family of homeodomain-containing proteins expressed selectively in lung, thyroid, and the central nervous system. To assess the role of TTF-1 and its phosphorylation during lung morphogenesis, mice bearing a mutant allele, in which seven serine phosphorylation sites were mutated, Titf1PM/PM, were generated by homologous recombination. Although heterozygous Titf1PM/+ mice were unaffected, homozygous Titf1PM/PM mice died immediately following birth.

Minimal lung and systemic responses to TNF-alpha in preterm sheep.

TNF-alpha has been associated with chorioamnionitis and the subsequent development of bronchopulmonary dysplasia in preterm infants. We asked whether bioactive recombinant ovine TNF-alpha could induce chorioamnionitis, lung inflammation, lung maturation, and systemic effects in fetal sheep. We compared the responses to IL-1alpha, a cytokine known to induce these responses in preterm sheep.

Increased IP-10 and MIG expression after intra-amniotic endotoxin in preterm lamb lung.

Subtraction hybridization was performed to explore changes in gene expression in the fetal lung after 20 mg of intra-amniotic (IA) endotoxin. Interferon-gamma-inducible 10-kd protein (IP-10) and monokine induced by interferon-gamma (MIG) constituted 20% of 102 endotoxin-induced clones identified in the preterm lamb lung. IP-10 (CXCL10) and MIG (CXCL9) are T-cell chemoattractants that have angiostatic properties.

Inhibition of nitric oxide restores surfactant gene expression following nickel-induced acute lung injury.

The role of nitric oxide (NO) in acute lung injury remains controversial. Although inhaled NO increases oxygenation in clinical trials, inhibiting NO-synthase (NOS) can be protective. To examine the latter, nickel-exposed mice were treated with saline or NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME).

The role of the receptor tyrosine kinase Ron in nickel-induced acute lung injury.

Acute lung injury (ALI), a severe respiratory syndrome, develops in response to numerous insults and responds poorly to therapeutic intervention. Recently, cDNA microarray analyses were performed that indicated several pathogenic responses during nickel-induced ALI, including marked macrophage activation. Macrophage activation is mediated, in part, via the receptor tyrosine kinase Ron.