[The association between portal vein thrombosis and rebleeding after non-urgent endoscopic treatment of esophagogastric varices].

Objective: To investigate the association between portal vein thrombosis and rebleeding after non-urgent endoscopic treatment of esophagogastric varices. Methods: The cirrhotic patients with esophagogastric varices diagnosed in the People's Hospital of Zhengzhou University from January 2017 to March 2023 were retrospectively collected. The patients were divided into thrombotic group and non-thrombotic group according to the presence or absence of portal vein thrombosis. The failure rate of endoscopic treatment and rebleeding rate in different periods were compared between the two groups. Receiver operating characteristic (ROC) curve was used to select the best cutoff value of gastric varicose diameter that affected total rebleeding during follow-up in both groups. The influencing factors of rebleeding within 12 and 36 months in both groups were analyzed, and the influencing factors of rebleeding within 36 months in thrombus group were further analyzed. Results: A total of 106 patients were enrolled, including 53 patients in the thrombotic group [male 37, female 16, aged 18-78 (54±13) years] and 53 patients in the non-thrombotic group [male 37, female 16, aged 27-83 (55±12) years]. The follow-up time of the two groups were (20±15) and (25±15) months, respectively. The total rebleeding rate in the thrombotic group was higher than that in the non-thrombotic group [30.2% (16/53) vs 13.2% (7/53), P˂0.05]. The rebleeding rates within 6, 12, 24 and 36 months in the thrombotic group were higher than those in the non-thrombotic group [18.9% (10/53) vs 5.7% (3/53), 18.9% (10/53) vs 5.7% (3/53), 28.3% (15/53) vs 9.4% (5/53), 30.2% (16/53) vs 11.3% (6/53), all P˂0.05]. The best cut-off value of the diameter of gastric varices that affects the total rebleeding in the two groups was 10.4 mm (10 mm was selected as the best cut-off value for the convenience of practical clinical application). Hemoglobin ˂ 85 g/L (HR=0.202, 95%CI: 0.043-0.953, P=0.043), 10 mm ˂ the diameter of GV ≤ 15 mm (HR=5.321, 95%CI: 1.161-24.390, P=0.031) and endoscopic variceal ligation combined with endoscopic tissue adhesive injection (EVL+ETAI) (HR=7.172, 95%CI: 1.910-26.930, P=0.004) were the risk factors for the first gastroesophageal variceal rebleeding within 12 months after non-urgent endoscopic treatment. EVL+ETAI (HR=3.811, 95%CI: 1.441-10.084, P=0.007) and portal vein thrombosis (HR=4.026, 95%CI: 1.483-10.932, P=0.006) were the risk factors for the first gastroesophageal variceal rebleeding within 36 months after non-urgent endoscopic treatment. The study found that, 10 mm ˂ the diameter of GV ≤ 15 mm (HR=7.503, 95%CI: 1.568-35.890, P=0.012) was the risk factor for rebleeding within 36 months in the thrombotic group. Conclusion: Portal vein thrombosis is a risk factor for rebleeding after non-urgent endoscopic treatment of esophagogastric varices.

MicroRNA-101, mitogen-activated protein kinases and mitogen-activated protein kinases phosphatase-1 in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is the prototype of human autoimmune disease in which various inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, IL-6 and interferon (IFN) play crucial pathogenic roles. The production of these cytokines is responsible for the mitogen-activated protein kinases (MAPKs), which can also generate mitogen-activated protein kinases phosphatases (MKPs). MKP-1, a prototypical member of the MKP family that can influence outcomes of autoimmune diseases and reduce the inflammatory cytokines by dephosphorylation of p38 and JNK MAPK, plays a critical role in the expression of inflammatory mediators at transcriptional and post-transcriptional levels. MicroRNA-101 (miR) is a small non-coding RNA that regulates the MAPK response by targeting MKP-1 mRNA 3'-UTR, and affects the secretion of the downstream inflammatory cytokines. However, the interaction among the above three in the pathogenesis of SLE has not previously been reported. This review discusses the current understanding of the role of the MAPK/MKP/miR-101 axis in regulating immune responses and the pathogenesis of SLE to provide new ideas for clinical treatment of SLE.

Sex-specific differences in the relationship between the single-nucleotide polymorphism rs2298804 of FCER1A and the susceptibility to systemic lupus erythematosus in a Chinese Han population.

BACKGROUND: IgE plays a important role in systemic lupus erythematosus (SLE). A recent study identified the high-affinity IgE receptor α-chain (FcεRIα) gene FCER1A as a susceptibility locus influencing total serum IgE levels. AIM: To investigate whether the single-nucleotide polymorphism (SNP) rs2298804 (251 A>G) of FCER1A is associated with SLE and its clinical characteristics in a Chinese Han population. METHODS: This case-control study enrolled 948 patients with SLE and 976 healthy controls. Precise phenotyping of patients was accomplished by means of a questionnaire and clinical examination. rs2298804 was genotyped using real-time fluorescence quantitative PCR. RESULTS: Compared with the healthy controls, patients with SLE had much lower frequencies of the AG genotype (OR = 0.26; 95% CI 0.194-0.374; P << 0.001) and G allele (OR = 0.45; 95% CI 0.36-0.55; P << 0.001). We also found a stronger association of the FCER1A exon SNP, rs2298804 (A/G), in females (OR = 0.42; 95%CI 0.34-0.53; P << 0.001) compared with males (OR = 0.52; 95% CI 0.28-0.97; P < 0.04). G-allele carriers are less likely to develop SLE than A-allele carriers. Although we did not find any significant correlation between the rs2298804 and the incidence of lupus nephritis, rs2298804 seemed to protect against proteinunia, fever and hypocomplementaemia in patients with SLE, but appeared to be a risk factor for photosensitivity and vasculitis. CONCLUSIONS: We found that rs2298804 seemed to have a protective effect against SLE in Chinese patients, especially women. It also protected against proteinunia, fever and hypocomplementaemia, but was a risk factor for photosensitivity and vasculitis.

The Ets protein Spi-B is expressed exclusively in B cells and T cells during development.

Spi-B and PU.1 are hematopoietic-specific transcription factors that constitute a subfamily of the Ets family of DNA-binding proteins. Here we show that contrary to previous reports, PU.1 and Spi-B have very different expression patterns. PU.1 is expressed at high levels in B cells, mast cells, megakaryocytes, macrophages, neutrophils, and immature erythroid cells and at lower levels in mature erythrocytes. PU.1 is completely absent from peripheral T cells and most T cell lines based on sensitive RT-PCR assays. In contrast, Spi-B is expressed exclusively in lymphoid cells and can be detected in early fetal thymus and spleen. In situ hybridizations of adult murine tissues demonstrate Spi-B mRNA in the medulla of the thymus, the white pulp of the spleen, and the germinal centers of lymph nodes. Spi-B expression is very abundant in B cells and both Spi-B mRNA and protein are detected in some T cells. In situ hybridization and Northern blot analysis suggest that Spi-B gene expression increases during B cell maturation and decreases during T cell maturation. Gel-retardation experiments show that Spi-B can bind to all putative PU.1 binding sites, but do not reveal any preferred Spi-B binding site. Finally, both PU.1 and Spi-B function as transcriptional activators of the immunoglobulin light-chain enhancer E lambda 2.4 when coexpressed with Pip (PU.1-interaction partner) in NIH-3T3 cells. Taken together, these data suggest that differences in patterns of expression between Spi-B and PU.1 distinguish the function of each protein during development of the immune system.

Clinical significance of raf-1 kinase inhibitor protein in oral squamous cell carcinoma and its role in cell metastasis.

OBJECTIVE: To detect the expression pattern of raf-1 kinase inhibitor protein (RKIP) in oral squamous cell carcinoma (OSCC) samples and to explore its clinical significance in OSCC metastasis. PATIENTS AND METHODS: Quantitative Real Time-Polymerase Chain Reaction (qRT-PCR) and Western blot assay were conducted to detect the expression of RKIP in OSCC tissues and cells. The relationship between RKIP expression and OSCC clinicopathological characteristics was statistically analyzed. Transwell assay, wound healing assay, and Western blot were used to detect the influence of RKIP on the metastasis ability of OSCC cells. RESULTS: RKIP was significantly downregulated in OSCC samples. Low expression of RKIP predicted high incidence of metastasis in OSCC patients. In vitro experiments demonstrated that overexpression of RKIP could significantly inhibit invasion and migration abilities of OSCC cells. CONCLUSIONS: RKIP was a novel factor involved in OSCC progression, which was a potential biomarker and therapeutic target for the patients.

Osteoinductive effects of tantalum and titanium on bone mesenchymal stromal cells and bone formation in ovariectomized rats.

OBJECTIVE: Although Tantalum (Ta) exhibits better osteoinductivity in healthy subjects when compared with titanium (Ti), the relative effects in osteoporosis remain unknown. MATERIALS AND METHODS: In this study, bone mesenchymal stromal cells of ovariectomized rats (OVX-rBMSCs) were seeded on Ta and Ti substrates for in vitro evaluation of cell viability, reactive oxygen species (ROS) production, alkaline phosphatase (ALP) activity, extracellular mineralization osteogenic gene and protein expression involved in bone morphogenetic protein (BMP2)/small mothers against decapentaplegic homologs 1 (Smad1) pathway. For in vivo assessment, Ta and Ti implants were embedded in femur defects of ovariectomized rats, followed by sequential fluorochrome labeling and histological staining. RESULTS: Compared to Ti, the Ta substrates demonstrated higher viable cell percentages (96.5 ± 0.26 vs. 88.17 ± 2.23%), lower ROS levels (65% vs. Ti), and enhanced ALP activity and extracellular matrix calcification. Reverse Transcription-Polymerase Chain Reaction and Western blot assays validated the better osteoinductive effect of Ta regarding small mothers against decapentaplegic homologs 1 (Smad1), runt-related transcription factor 2, bone morphogenetic protein (BMP2), and ALP expression at both the mRNA (1.5-2-fold) and protein (1.2-1.8-fold) levels. BMP2/Smad1 signaling over-expression or knockdown yielded significantly enhanced or deteriorated OVX-rBMSC osteogenesis on the two surfaces. In addition, the Ta group revealed more new bone formation (1.3-1.5-fold vs. Ti) and slightly better bone-implant contact (31.82 ± 4.07 vs. 25.2-3.84% at 8 weeks post-implantation, p = 0.052) without the contribution of specific surface structures. CONCLUSIONS: In comparison to Ti, Ta reveals better biocompatibility and osteoinductivity to OVX-rBMSCs, and the preferential Ta osteoinductivity may reflect its greater potential to trigger the BMP2/Smad1 cascade. Thus," in front of "Ta". Ta appears preferable to Ti as a bone-implant surface material under osteoporosis conditions.

Adenovirus-mediated over-expression of the cyclin/cyclin-dependent kinase inhibitor, p21 inhibits vascular smooth muscle cell proliferation and neointima formation in the rat carotid artery model of balloon angioplasty.

Vascular smooth muscle cell (VSMC) proliferation after arterial injury is important in the pathogenesis of a number of vascular proliferative disorders, including atherosclerosis and restenosis after balloon angioplasty. Thus, a better understanding of the molecular mechanisms underlying VSMC proliferation in response to arterial injury would have important therapeutic implications for patients with atherosclerotic vascular disease. The p21 protein is a negative regulator of mammalian cell cycle progression that functions both by inhibiting cyclin dependent kinases (CDKs) required for the initiation of S phase, and by binding to and inhibiting the DNA polymerase delta co-factor, proliferating cell nuclear antigen (PCNA). In this report, we show that adenovirus-mediated over-expression of human p21 inhibits growth factor-stimulated VSMC proliferation in vitro by efficiently arresting VSMCs in the G1 phase of the cell cycle. This p21-associated cell cycle arrest is associated both with significant inhibition of the phosphorylation of the retinoblastoma gene product (Rb) and with the formation of complexes between p21 and PCNA in VSMCs. In addition, we demonstrate that localized arterial infection with a p21-encoding adenovirus at the time of balloon angioplasty significantly reduced neointimal hyperplasia in the rat carotid artery model of restenosis. Taken together, these studies demonstrate the important role of p21 in regulating Rb phosphorylation and cell cycle progression in VSMC, and suggest a novel cytostatic gene therapy approach for restenosis and related vascular proliferative disorders.

Pax3 is required for enteric ganglia formation and functions with Sox10 to modulate expression of c-ret.

Hirschsprung disease and Waardenburg syndrome are human genetic diseases characterized by distinct neural crest defects. Patients with Hirschsprung disease suffer from gastrointestinal motility disorders, whereas Waardenburg syndrome consists of defective melanocyte function, deafness, and craniofacial abnormalities. Mutations responsible for Hirschsprung disease and Waardenburg syndrome have been identified, and some patients have been described with characteristics of both disorders. Here, we demonstrate that PAX3, which is often mutated in Waardenburg syndrome, is required for normal enteric ganglia formation. Pax3 can bind to and activate expression of the c-RET gene, which is often mutated in Hirschsprung disease. Pax3 functions with Sox10 to activate transcription of c-RET, and SOX10 mutations result in Waardenburg-Hirschsprung syndrome. Thus, Pax3, Sox10, and c-Ret are components of a neural crest development pathway, and interruption of this pathway at various stages results in neural crest-related human genetic syndromes.

A serum response factor-dependent transcriptional regulatory program identifies distinct smooth muscle cell sublineages.

The SM22alpha promoter has been used as a model system to define the molecular mechanisms that regulate smooth muscle cell (SMC) specific gene expression during mammalian development. The SM22alpha gene is expressed exclusively in vascular and visceral SMCs during postnatal development and is transiently expressed in the heart and somites during embryogenesis. Analysis of the SM22alpha promoter in transgenic mice revealed that 280 bp of 5' flanking sequence is sufficient to restrict expression of the lacZ reporter gene to arterial SMCs and the myotomal component of the somites. DNase I footprint and electrophoretic mobility shift analyses revealed that the SM22alpha promoter contains six nuclear protein binding sites (designated smooth muscle elements [SMEs] -1 to -6, respectively), two of which bind serum response factor (SRF) (SME-1 and SME-4). Mutational analyses demonstrated that a two-nucleotide substitution that selectively eliminates SRF binding to SME-4 decreases SM22alpha promoter activity in arterial SMCs by approximately 90%. Moreover, mutations that abolish binding of SRF to SME-1 and SME-4 or mutations that eliminate each SME-3 binding activity totally abolished SM22alpha promoter activity in the arterial SMCs and somites of transgenic mice. Finally, we have shown that a multimerized copy of SME-4 (bp -190 to -110) when linked to the minimal SM22alpha promoter (bp -90 to +41) is necessary and sufficient to direct high-level transcription in an SMC lineage-restricted fashion. Taken together, these data demonstrate that distinct transcriptional regulatory programs control SM22alpha gene expression in arterial versus visceral SMCs. Moreover, these data are consistent with a model in which combinatorial interactions between SRF and other transcription factors that bind to SME-4 (and that bind directly to SRF) activate transcription of the SM22alpha gene in arterial SMCs.

Analysis of SM22alpha-deficient mice reveals unanticipated insights into smooth muscle cell differentiation and function.

SM22alpha is a 22-kDa smooth muscle cell (SMC) lineage-restricted protein that physically associates with cytoskeletal actin filament bundles in contractile SMCs. To examine the function of SM22alpha, gene targeting was used to generate SM22alpha-deficient (SM22(-/-LacZ)) mice. The gene targeting strategy employed resulted in insertion of the bacterial lacZ reporter gene at the SM22alpha initiation codon, permitting precise analysis of the temporal and spatial pattern of SM22alpha transcriptional activation in the developing mouse. Northern and Western blot analyses confirmed that the gene targeting strategy resulted in a null mutation. Histological analysis of SM22(+/-LacZ) embryos revealed detectable beta-galactosidase activity in the unturned embryonic day 8.0 embryo in the layer of cells surrounding the paired dorsal aortae concomitant with its expression in the primitive heart tube, cephalic mesenchyme, and yolk sac vasculature. Subsequently, during postnatal development, beta-galactosidase activity was observed exclusively in arterial, venous, and visceral SMCs. SM22alpha-deficient mice are viable and fertile. Their blood pressure and heart rate do not differ significantly from their control SM22alpha(+/-) and SM22alpha(+/+) littermates. The vasculature and SMC-containing tissues of SM22alpha-deficient mice develop normally and appear to be histologically and ultrastructurally similar to those of their control littermates. Taken together, these data demonstrate that SM22alpha is not required for basal homeostatic functions mediated by vascular and visceral SMCs in the developing mouse. These data also suggest that signaling pathways that regulate SMC specification and differentiation from local mesenchyme are activated earlier in the angiogenic program than previously recognized.

Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse.

The basic helix-loop-helix-PAS (bHLH-PAS) protein ARNT is a dimeric partner of the Ah receptor (AHR) and hypoxia inducible factor 1 alpha(HIF1 alpha). These dimers mediate biological responses to xenobiotic exposure and low oxygen tension. The recent cloning of ARNT and HIF1(homologues (ARNT2 and HIF2 alpha) indicates that at least six distinct bHLH-PAS heterodimeric combinations can occur in response to a number of environmental stimuli. In an effort to understand the biological relevance of this combinatorial complexity, we characterized their relative expression at a number of developmental time points by parallel in situ hybridization of adjacent tissue sections. Our results reveal that in general there is limited redundancy in the expression of these six transcription factors and that each of these bHLH-PAS members displays a unique pattern of developmental expression emerging as early as embryonic day 9.5.

Characterization of Wnt gene expression in developing and postnatal hair follicles and identification of Wnt5a as a target of Sonic hedgehog in hair follicle morphogenesis.

Mutations in WNT effector genes perturb hair follicle morphogenesis, suggesting key roles for WNT proteins in this process. We show that expression of Wnts 10b and 10a is upregulated in placodes at the onset of follicle morphogenesis and in postnatal hair follicles beginning a new cycle of hair growth. The expression of additional Wnt genes is observed in follicles at later stages of differentiation. Among these, we find that Wnt5a is expressed in the developing dermal condensate of wild type but not Sonic hedgehog (Shh)-null embryos, indicating that Wnt5a is a target of SHH in hair follicle morphogenesis. These results identify candidates for several key follicular signals and suggest that WNT and SHH signaling pathways interact to regulate hair follicle morphogenesis.

Establishment and characterization of a megakaryoblast cell line with amplification of MLL.

A new cell line with megakaryoblastic features, designated UoC-M1, was established from the malignant cells of a 68-year-old patient with acute myeloid leukemia. The patient's leukemic cells reacted with alpha-naphthyl acetate esterase and acid phosphatase and expressed CD7, CD24, CD34, CD38, CD45, HLA-DR and CD61. Cytogenetic analysis of the patient's malignant cells (and of the UoC-M1 cells) showed a human, male hypodiploid karyotype with many chromosome rearrangements and marker chromosomes. Spectral karyotyping (SKY) analysis complemented the G-banded karyotyping and clarified several chromosomal translocations and identified the marker chromosomes. Fluorescence in situ hybridization (FISH) and SKY analysis demonstrated that one marker chromosome contained three segments of chromosome 9 interspersed with three segments of chromosome 11, as well as a portion of chromosome 19. FISH analysis with a probe for MLL revealed that the UoC-M1 cells contained four copies of the MLL gene. Southern blot analysis determined that the MLL gene had a germline profile while Northern and Western analyses showed that the MLL mRNAs and protein were of the appropriate sizes. This is the first report of amplification of the MLL gene which may be an additional mechanism of leukemogenesis or disease progression.

Reduced graphene oxides: the thinnest and most lightweight materials with highly efficient microwave attenuation performances of the carbon world.

In this work, reduced graphene oxide (r-GO) and graphite nanosheet (GN) were obtained via the chemical approach. Furthermore, r-GO composites and GN composites were prepared with a paraffin wax host. r-GO composites show high dielectric properties and electromagnetic interference shielding efficiency (EMI SE). Compared with the GN composites, the loss tangent and EMI SE of the r-GO composites with the same mass ratio are enhanced ∼5 to 10 times and ∼3 to 10 times, respectively. The enhanced attenuation capacity arises from higher specific surface area, clustered defects and residual bonds of the r-GOs, which increase the polarization loss, scattering and conductivity of the composite. Moreover, the higher conductivity of r-GO composites leads to higher EMI SE compared with that of GN composites. These results suggest that r-GOs are highly promising fillers for microwave attenuation in the carbon family and that r-GO composites are high-performance EMI shielding materials with application anticipated to many fields.

Formation of nanostructure and nano-hardness characterization on the meso-scale workpiece by a novel laser indirect shock forming method.

The meso-scale workpiece with greatly enhanced mechanical properties is potential to be widely used in the electronics productions and micro-electro mechanical systems. In this study, it demonstrates that the meso-scale cup-shape workpiece with good geometry can be obtained by a novel laser indirect shock forming method. After the forming process, the mechanical properties and microstructures of the formed workpiece were characterized. By transmission electron microscope observation, it was found that a mixed refined microstructure consisting of nano-scale twins embedded in nano-sized grains was produced at the center of the formed sample. Formation of these nanograins could be mainly attributed to two mechanisms: twin-twin intersections and twin∕matrix lamellae fragmentation. By nanoindentation tests, it reveals that the hardness of the sample has increased greatly after laser shock forming and the hardness increases with the laser energy. The elevated hardness originates from a considerable number of nano-scale twins and nanograins, which possess a pretty high strength due to the significant effects of grain boundary strengthening and twin boundary strengthening.

Minimally invasive endoscopic-assisted resection of benign tumors in the accessory parotid gland: 5 case studies.

BACKGROUND: A modified Blair's incision or standard facelift incision is recommended to remove tumors in the accessory parotid gland. These incisions frequently result in long and visible scars. Therefore, the authors have introduced an endoscopic approach via a small preauricular incision to achieve excision of benign tumors in the accessory parotid gland. METHODS: The endoscopic surgical technique was performed on 5 patients with benign tumors in the accessory parotid gland. RESULTS: Endoscopic-assisted resection of the benign tumors in the accessory parotid gland was feasible in all 5 patients. This procedure lasted 105 minutes on average. Facial paralysis, salivary fistula, and ear-lobular numbness were not found postoperatively. The follow-up period was 1 year, during which no Frey's syndrome and recurrence were found. All preauricular scars were aesthetically satisfactory. CONCLUSIONS: The minimally invasive endoscopic approach via a small preauricular incision is an optional method of the accessory parotid gland benign tumor resection.

Stable delivery of physiologic levels of recombinant erythropoietin to the systemic circulation by intramuscular injection of replication-defective adenovirus.

A number of inherited and acquired serum protein deficiencies including hemophilias A and B, diabetes mellitus, and the erythropoietin-responsive anemias are currently treated with repeated subcutaneous or intravenous infusions of purified or recombinant proteins. The development of an in vivo gene-transfer approach to deliver physiologic levels of recombinant proteins to the systemic circulation would represent a significant advance in the treatment of these disorders. Here we describe the construction of a replication-defective adenovirus (AdEF1hEpo) containing the human erythropoietin (hEpo) cDNA under the transcriptional control of the cellular elongation factor 1 alpha (EF1 alpha) promoter and the 4F2 heavy chain (4F2HC) enhancer. Neonatal CD-1 and adult SCID mice injected once intramuscularly (i.m.) with 10(7) to 10(9) plaque-forming units (pfu) of this virus displayed significant dose-dependent elevations of serum hEpo levels and increased hematocrits, which were stable over the 4-month time course of these experiments. Adenovirus injected i.m. remained localized at the site of injection and there was no evidence of either systemic infection or a localized inflammatory response. These results suggest that i.m. injection of recombinant replication-defective adenovirus vectors may serve as a paradigm for the treatment of human serum protein deficiencies.

Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors.

Epithelial gene expression in the lung is thought to be regulated by the coordinate activity of several different families of transcription factors including the Fox family of winged-helix/forkhead DNA-binding proteins. In this report, we have identified and characterized two members of this Fox gene family, Foxp1 and Foxp2, and show that they comprise a new subfamily of Fox genes expressed in the lung. Foxp1 and Foxp2 are expressed at high levels in the lung as early as E12.5 of mouse development with Foxp2 expression restricted to the airway epithelium. In addition, Foxp1 and Foxp2 are expressed at lower levels in neural, intestinal, and cardiovascular tissues during development. Upon differentiation of the airway epithelium along the proximal-distal axis, Foxp2 expression becomes restricted to the distal alveolar epithelium whereas Foxp1 expression is observed in the distal epithelium and mesenchyme. Foxp1 and Foxp2 can regulate epithelial lung gene transcription as was demonstrated by their ability to dramatically repress the mouse CC10 promoter and, to a lesser extent, the human surfactant protein C promoter. In addition, GAL4 fusion proteins encoding subdomains of Foxp1 and Foxp2 demonstrate that an independent and homologous transcriptional repression domain lies within the N-terminal end of the proteins. Together, these studies suggest that Foxp1 and Foxp2 are important regulators of lung epithelial gene transcription.

GATA-5: a transcriptional activator expressed in a novel temporally and spatially-restricted pattern during embryonic development.

Members of the GATA family of zinc finger transcription factors regulate critical steps of cellular differentiation during vertebrate development. In the studies described in this report, we have isolated and functionally characterized the murine GATA-5 cDNA and protein and defined the temporal and spatial pattern of GATA-5 gene expression during mammalian development. The amino terminus of the mouse GATA-5 protein shares high level amino acid sequence identity with the murine GATA-4 and -6 proteins, but not with other members of the GATA family. GATA-5 binds to the functionally important CEF-1 nuclear protein binding site in the cardiac-specific slow/cardiac troponin C (cTnC) transcriptional enhancer and overexpression of GATA-5 transactivates the cTnC enhancer in noncardiac muscle cell lines. During embryonic and postnatal development, the pattern of GATA-5 gene expression differs significantly from that of other GATA family members. In the primitive streak embryo, GATA-5 mRNA is detectable in the precardiac mesoderm. Within the embryonic heart, the GATA-5 gene is expressed within the atrial and ventricular chambers (ED 9.5), becomes restricted to the atrial endocardium (ED 12.5), and is subsequently not expressed in the heart during late fetal and postnatal development. Moreover, coincident with the earliest steps in lung development, only the GATA-5 gene is expressed within the pulmonary mesenchyme. Finally, the GATA-5 gene is expressed in tissue-restricted subsets of smooth muscle cells (SMCs), including bronchial SMCs and SMCs in the bladder wall. These data are consistent with a model in which GATA-5 performs a unique temporally and spatially restricted function in the embryonic heart and lung. Moreover, these data suggest that GATA-5 may play an important role in the transcriptional program(s) that underlies smooth muscle cell diversity.