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PubMed2005

A transcriptional pathway for cell separation in fission yeast.

Numerous genes are transcriptionally activated and repressed in a cell cycle-dependent manner. We have recently reported the global gene expression program during the cell cycle in fission yeast (S. pombe). Among the periodically expressed fission yeast genes, a large proportion shows peak transcript levels during mitosis. Many of these genes are regulated by a transcriptional cascade involving two transcription factors: the forkhead protein Sep1p which activates the zinc finger protein Ace2p. A main function of the Sep1p-Ace2p transcriptional pathway is to trigger the separation of daughter cells after cytokinesis. Absence of Sep1p, Ace2p, or some of their target genes leads to a hyphal-like growth pattern with chains of connected cells. Yeast cells probably evolved from filamentous fungi. It is possible that the Sep1p-Ace2p pathway contributed to the emergence of proliferation through single cells, and that this regulatory pathway can still be modulated to adjust growth modes depending on environmental conditions. Here, various properties of the Sep1p-Ace2p transcriptional pathway and mechanisms for cell separation are discussed in the context of recent findings.

Cell Cycle↗

PubMed2005

Crosstalk between p53 and FOXO transcription factors.

Recent studies find striking similarities between p53 and the FOXO family of forkhead transcription factors. Both transcription factors can be posttranslationally modified, for example, by acetylation and phosphorylation. They regulate a number of genes in common. Upregulation of either p53 or FKHRL1 leads to cell cycle arrest or apoptosis, depending on cellular context and type of stress. While these findings suggest that p53 and FOXO may parallel in their functions, our recent report demonstrates cross talk between these two transcription factors in vivo. Since both p53 and FOXO have been described as potential drug targets in cancer therapy, we believe understanding their functional interactions as well as the signaling pathways involved will be important to direct their clinical application.

Acetylation↗

PubMed2001

Synergistic action of HNF-3 and Brachyury in the notochord differentiation of ascidian embryos.

In vertebrate embryos, the class I subtype forkhead domain gene HNF-3 is essential for the formation of the endoderm, notochord and overlying ventral neural tube. In ascidian embryos, Brachyury is involved in the formation of the notochord. Although the results of previous studies imply a role of HNF-3 in notochord differentiation in ascidian embryos, no experiments have been carried out to address this issue directly. Therefore the present study examined the developmental role of HNF-3 in ascidian notochord differentiation. When embryos were injected with a low dose of HNF-3 mRNA, their tails were shortened and when embryos were injected with a high dose of HNF-3 mRNA, which was enough to inhibit differentiation of epidermis and muscle, no obvious ectopic differentiation of endoderm or notochord cells was observed. However, co-injection of HNF-3 mRNA along with Brachyury mRNA resulted in ectopic differentiation of notochord cells in the animal hemisphere, suggesting that HNF-3 acts synergistically with Brachyury in ascidian notochord differentiation. Notochord differentiation of the A-line precursor cells depends on inducing signal(s) from endodermal cells, which can be mimicked by bFGF treatment. Treatment of notochord precursor cells isolated from the 32-cell stage embryoswith bFGF resulted in upregulation of both the HNF-3 and Brachyury genes.

Amino Acid Sequence↗

PubMed2002

Ocular developmental abnormalities and glaucoma associated with interstitial 6p25 duplications and deletions.

PURPOSE: Mutations in the forkhead transcription factor gene FOXC1 on 6p25 cause a range of ocular developmental abnormalities, with associated glaucoma. However, FOXC1 mutations have not been found in all similarly affected pedigrees mapping to this interval. This study was undertaken to investigate the potential role of 6p25 rearrangements in causing such phenotypes. METHODS: Two large families with autosomal dominant iris hypoplasia and early-onset glaucoma, 21 probands with Axenfeld-Rieger phenotypes not attributable to PITX2 mutations, and 7 individuals with documented 6p25 cytogenetic rearrangements, were investigated by genotyping and fluorescence in situ hybridization, with markers and probes from the 6p25 region. RESULTS: Interstitial 6p25 duplications were present in the unrelated families with iris hypoplasia, whereas an interstitial 6p25 deletion was identified in one Axenfeld-Rieger pedigree. Larger cytogenetic rearrangements, leading to trisomy or monosomy of the 6p25 region, resulted in microcornea and Rieger syndrome phenotypes, respectively. All the rearrangements encompassed FOXC1, increasing or decreasing the number of FOXC1 copies present, and appeared to correlate with the phenotypes observed. CONCLUSIONS: These findings represent the first example of both interstitial duplications and deletions cosegregating with a human developmental disorder that is attributable to altered dose of transcription factor. The data presented provide additional evidence for the pathogenicity of altered gene dosage of FOXC1 and suggest that a common mechanism is responsible for rearrangements of 6p25.

Base Sequence↗

PubMed2002

Identification of FOXC1 as a TGF-beta1 responsive gene and its involvement in negative regulation of cell growth.

We cloned the forkhead box C1 (FOXC1) gene, a member of the forkhead/winged-helix transcription factor family, as a transforming growth factor-beta1 (TGF-beta1) responsive gene. We showed that TGF-beta1 upregulated transcription of FOXC1 in several human cancer cell lines. Ectopic expression of FOXC1 cDNA in HeLa cells, which lack both copies of the FOXC1 allele, restores the potential of TGF-beta1 to inhibit cell growth by arresting cells in the G0/G1 phase. In addition, screens of primary endometrial and ovarian cancers revealed homozygous deletion of FOXC1 in 6.7% of them, one nonsense and one missense mutation of FOXC1, and transcriptional silencing in 11.7% of primary cancers. Evidence that a significant fraction of primary cancers exhibited somatic mutations suggests that FOXC1 functions as a tumor suppressor through TGF-beta1 mediated signals.

Cell Cycle↗

PubMed2002

Novel mutation in FOXC1 wing region causing Axenfeld-Rieger anomaly.

PURPOSE: To determine the possible molecular genetic defect underlying Axenfeld-Rieger anomaly (ARA) and to identify the pathogenic mutation causing this anterior segment dysgenesis in an Indian pedigree. METHODS: The FOXC1 gene was amplified from genomic DNA of members of an ARA-affected family and control subjects using four novel sets of primers. The amplicons were directly sequenced, and the sequences were analyzed to identify the disease-causing mutation. RESULTS: A heterozygous novel missense mutation was identified in the coding region of the FOXC1 gene in all three patients in this family. Consistent with the autosomal dominant inheritance pattern, the mutation segregated with the disease phenotype and was fully penetrant. The mutation was found in the wing region of the highly conserved forkhead domain of the FOXC1 gene and resulted in a very severe phenotype leading to blindness. CONCLUSIONS: This is the first study to demonstrate that a mutation in the FOXC1 wing region can cause an anterior segment dysgenesis of the eye. This mutation resulted in blindness in the ARA-affected family, and the findings suggest that the FOXC1 wing region has a functional role in the normal development of the eye. Moreover, this is the first study from India to report the genetic etiology of Axenfeld-Rieger anomaly. Genotype-phenotype correlations of FOXC1 may help in establishing the disease prognosis and also in understanding the clinical and genetic heterogeneity associated with various anterior segment dysgenesis caused by this gene.

Adult↗

PubMed2003

Screening for mutations in BMP4 and FOXC1 genes in congenital anomalies of the kidney and urinary tract in humans.

Recent studies have demonstrated in mice that bone morphogenetic protein 4 (BMP4) and forkhead transcription factor 1 (FOXC1) are involved in the organogenesis of the kidney and urinary tract and that derangement of either gene, BMP4 or FOXC1, leads to development of congenital anomalies of the kidney and urinary tract (CAKUT). In order to determine whether human CAKUT is associated with abnormalities in BMP4 or FOXC1, we established a PCR-based methodology for the DNA sequence analysis of BMP4 and FOXC1 in humans. Our initial screening identified an insertion mutation in FOXC1 with a triplet GGC in three of the seven patients with CAKUT. In the present study, no mutation was detected in the coding sequence of BMP4.

Animals↗

PubMed2004

Human FOX gene family (Review).

Human Forkhead-box (FOX) gene family consists of at least 43 members, including FOXA1, FOXA2, FOXA3, FOXB1, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3, FOXD4, FOXD5 (FOXD4L1), FOXD6 (FOXD4L3), FOXE1, FOXE2, FOXE3, FOXF1, FOXF2, FOXG1 (FOXG1B), FOXH1, FOXI1, FOXJ1, FOXJ2, FOXJ3, FOXK1, FOXK2, FOXL1, FOXL2, FOXM1, FOXN1, FOXN2 (HTLF), FOXN3 (CHES1), FOXN4, FOXN5 (FOXR1), FOXN6 (FOXR2), FOXO1 (FOXO1A), FOXO2 (FOXO6), FOXO3 (FOXO3A), FOXO4 (MLLT7), FOXP1, FOXP2, FOXP3, FOXP4, and FOXQ1. FOXE3-FOXD2 (1p33), FOXQ1-FOXF2-FOXC1 (6p25.3), and FOXF1-FOXC2-FOXL1 (16q24.1) loci are FOX gene clusters within the human genome. Members of FOX subfamilies A-G, I-L and Q were grouped into class 1 FOX proteins, while members of FOX subfamilies H and M-P were grouped into class 2 FOX proteins. C-terminal basic region within the FOX domain was the common feature of class 1 FOX proteins. FOXH1 and FOXO1 mRNAs are expressed in human embryonic stem (ES) cells. FOXC1, FOXC2, FOXE1, FOXE3, FOXL2, FOXN1, FOXP2 and FOXP3 genes are mutated in human congenital disorders. FOXA1 gene is amplified and over-expressed in esophageal and lung cancer. FOXM1 gene is up-regulated in pancreatic cancer and basal cell carcinoma due to the transcriptional regulation by Sonic Hedgehog (SHH) pathway. FOXO1 gene is fused to PAX3 or PAX7 genes in rhabdomyosarcoma. FOXO3 and FOXO4 genes are fused to MLL gene in hematological malignancies. Deregulation of FOX family genes leads to congenital disorders, diabetes mellitus, or carcinogenesis. Expression profiles, genetic alterations and epigenetic changes of FOX family genes as well as binding proteins and target genes of FOX family transcription factors should be comprehensively investigated to develop novel therapeutics and preventives for human diseases.

Amino Acid Sequence↗

PubMed2004

Characterization of human FOXN4 gene in silico.

Forkhead-box (FOX) superfamily genes are implicated in carcinogenesis through gene amplification, retroviral integration and chromosomal translocation. FOX superfamily genes within the human genome are classified into 17 or 18 families, designated FOX# (# is alphabet A-Q or R). FOXN1, FOXN2 (HTLF), FOXN3 (CHES1), FOXN4, FOXN5 (FOXR1) and FOXN6 (FOXR2) genes constitute the FOXN gene family. Here, we characterized human FOXN4 gene by using bioinformatics. FOXN4 gene at human chromosome 12q24.12 was found to encode three isoforms. FOXN4 isoform 1 (representative transcript), encoding a 518-aa protein, consists of exons 1-10. FOXN4 isoform 2 (NM_ 213596.1), encoding a 337-aa protein, consists of exons 1, 2, 7v, 8-10. FOXN4 isoform 3, encoding a 314-aa protein, consists of exons 1-5, 7-10. Codon 205-518 of isoform 1 was conserved in isoforms 2 and 3. FOXN4 mRNA was expressed in testis, embryonic stem (ES) cells, uterus tumors, and leiomyosarcoma. FOXN4 was most homologous to FOXN1 among human FOXN family members. FOXN4 and FOXN1 showed 41.3% total-amino-acid identity. FOX domain (codon 192-305 of FOXN4) was well conserved among mammalian FOXN family members. FN14 domain (codon 367-456 of FOXN4) was identified as the novel domain conserved among FOXN4 and FOXN1 orthologs. FOXN4 and FOXN1 orthologs were found to share the common domain structure, consisting of FOX and FN14 domains. This is the first report on comprehensive characterization of the human FOXN4 gene as well as on identification of the FN14 domain.

Amino Acid Sequence↗

PubMed2005

Expression of the FOXP1 transcription factor is strongly associated with inferior survival in patients with diffuse large B-cell lymphoma.

Gene expression profiling studies have reported up-regulated mRNA expression of the FOXP1 forkhead transcription factor in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to investigate the prognostic importance of FOXP1 protein expression in an independent series of DLBCL.First, the specificity of our FOXP1 monoclonal antibody was verified by confirming that it did not recognize the closely related FOXP2, FOXP3, or FOXP4 proteins. FOXP1 protein expression was then analyzed by immunohistochemistry using a DLBCL tissue microarray constructed from 101 previously untreated de novo cases from the British Columbia Cancer Agency. FOXP1 expression was scored as either positive (>30% positive nuclei) or negative (<30% positive nuclei). The overall survival curves clearly showed that patients grouped as FOXP1-positive (40%) had a significantly decreased overall survival (P = 0.0001). FOXP1-positive patients had a median overall survival of 1.6 years compared with 12.2 years in FOXP1-negative cases. In addition, FOXP1-positive patients showed a clear trend to earlier progression in comparison to the FOXP1-negative patients. The analysis of FOXP1 expression within low, medium, and high International Prognostic Index groupings found that FOXP1-negative patients had better overall survival within each group indicating that FOXP1 expression has predictive value independent of the International Prognostic Index subgrouping, a finding that was confirmed in multivariate analysis. These initial results suggest that FOXP1 expression may be important in DLBCL pathogenesis.

Adult↗

PubMed2005

[Expression of Tim-3 in tumor tissue and its role in the induction of tumor immune tolerance].

AIM: To explore the role of T cell immunoglobulin- and mucin- domain containing molecule-3 (Tim-3) in the induction of tumor immune tolerance by investigating the expression of two types of Tim-3 at the early stage of tumorigenesis and the temporal-spatial relationship between the expression of Tim-3 and other immuno-inhibitory genes in tumor. METHODS: By using semi-quantitative RT-PCR method, we investigated the expression of Tim-3, forkhead box P3 (Foxp3), cytotoxic T lymphocyte antigen 4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR), TGF-beta, IL-10 and IFN-gamma at different time in tumor of tumor-bearing mice. Meanwhile, the growth of tumor was determined. RESULTS: At the early stage of tumorigenesis, sTim-3 was expressed before flTim-3 in tumor. When flTim-3 was expressed, the expression of sTim-3 was down-regulated. The expression of Foxp3, and GITR was simultaneous with that of flTim-3 and was up-regulated gradually with tumor growth. The expression of CTLA-4 was earlier than that of flTim-3 and also up-regulated gradually. The expression of flTim-3 and Foxp3 was also consistent with each other in tissue distribution. The growth of tumor was postively correlated with the expression of flTim-3, Foxp3, and CTLA-4 and negatively with the expression of sTim-3. CONCLUSION: Along with the growth of tumor, immune tolerance was gradually established in tumor. flTim-3 but not sTim-3 may induce tumor immunological tolerance.

Animals↗

PubMed2005

SIRT1 is critical regulator of FOXO-mediated transcription in response to oxidative stress.

Forkhead transcription factor, DAF-16, regulates genes that contribute both to longevity and resistance to various stresses in C. elegans. We and others have reported that members of the FOXO, mammalian homologs of DAF-16, also regulate genes related to stress resistance, such as GADD45. The NAD-dependent protein deacetylase, SIR2, is required for life span extension in yeast induced by caloric restriction, which also increases longevity in a wide variety of other organisms, including mammals. Sir2.1, a homolog of yeast SIR2, also extends life span by acting in a DAF-16 signaling pathway in C. elegans. We demonstrate that mammalian SIRT1 (Sir2alpha) physiologically interacts with FOXO. Acetylation of FOXO4, by the transcriptional coactivator p300, counteracted transcriptional activation of FOXO4 by p300. In contrast, mammalian SIRT1 was found to bind to FOXO4, catalyze its deacetylation in an NAD-dependent manner, and thereby increase its transactivation activity. The activity of FOXO4 is suppressed or enhanced by SIRT1 inhibitor, nicotinamide, or its activator, resveratrol, respectively. In response to oxidative stress, FOXO accumulates within the nucleus and induces GADD45 expression. FOXO-mediated GADD45 induction is markedly impaired in the cell, which depleted SIRT1 expression by RNA-interference. These results indicate that mammalian SIRT1 plays a pivotal role for FOXO function via NAD-dependent deacetylation in response to oxidative stress, and thereby may contribute to cellular stress resistance and longevity.

Acetylation↗

PubMed2006

Expression of Foxp3 in non-small cell lung cancer patients is significantly higher in tumor tissues than in normal tissues, especially in tumors smaller than 30 mm.

Active suppression by CD4+CD25+ T regulatory cells (T regs) plays an important role in the down-regulation of T cell responses to foreign and self-antigens. Thus far, the potential role of T regs in human tumors has been reported. T reg-mediated suppression of antitumor immune responses may partly explain the poor clinical response to vaccine-based immunotherapy for human cancer. The forkhead transcription factor Foxp3 is a critical regulator of T regs development and function. Foxp3 represents a specific marker for the T regs. In this study, we measured the Foxp3 mRNA expression in tumors and in normal tissues from 46 patients with non-small cell lung carcinoma (NSCLC), and tumor tissues showed a significantly higher expression of Foxp3 mRNA than normal tissues. The expression of Foxp3 mRNA and the tumor diameter were inversely proportional. These results suggest that T regs expressing Foxp3 selectively accumulate in tumor tissues of NSCLC and contribute to antitumor immune dysfunction, especially in the early stages.

Adult↗

PubMed2006

PI3-kinase and the control of T cell growth and proliferation by FoxOs.

Numerous cancers are caused by an uncontrolled uncontrolled activity of the PI3-kinase pathway. The proto-oncogene Akt, one of its main effectors, commands several molecular switches involved in cell survival and proliferation. One of these switches is represented by a group of related molecules belonging to the Forkhead family of transcription factors, called FoxOs. FoxOs negatively control cell cycle entry and this process emerges now as a mainstream mechanism used by various cell types to escape cell quiescence. In the light of recent works, FoxOs seem also to have a key role in the proliferative response of immune cells, especially in the clonal expansion of T lymphocytes induced by antigen. Experimental evidence supporting a relationship in T cells between PI3-kinase metabolism and these growth suppressive genes will be described in this mini-review.

Animals↗

PubMedDate not supplied

CD4+CD25+ regulatory T cells in patients with Behçet's disease.

OBJECTIVE: To investigate whether the CD4+CD25+ regulatory T cell (Treg) population, which plays important role in autoimmune diseases is related to the pathophysiology of Behçet's disease (BD). METHODS: Forty-two patients with BD (20 patients in active disease) fulfilling the criteria of the International Study Group of BD. Twenty age-matched healthy controls were studied. We analyzed CD4+CD25+/high T cells and the mRNA expression of Foxp3, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and transforming growth factor beta (TGF-beta) in BD. We have studied the ability of CD4+CD25+ (Treg) to regulate proliferation of CD4+CD25- T cells during active BD stage. RESULTS: Active BD patients had significantly higher CD4+CD25+/high T cells, as compared with BD in the remission stage, and healthy controls. There was no significant differences in the CD4+ CD25+/high T cells expression between healthy controls and remission BD. In active BD, mRNA for Forkhead box p3 (Foxp3) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were highly expressed when compared to remission BD and healthy controls. There was no differences in the mRNA expression for TGF-beta in active BD, remission BD and healthy controls. Functionally, CD4+CD25+/high T cells in active BD were impaired in their proliferative responses and could suppress the proliferation of their CD4+CD25- counterparts. CONCLUSION: These data demonstrate that CD4+CD25+ Treg cells, with the potential to regulate suppression of effector T cells, were increased in the peripheral circulation of active BD patients. The role of CD4+CD25+/high T cells in the regulatory process of the inflammation in active BD, could be taken in account.

Adult↗

PubMed2026

[Effects and mechanisms of Jiawei Yigong San on the Th17/Treg balance in food allergy].

Objective To explore the effects and mechanisms of Jiawei Yigong San (JWYGS) on the T helper type 17 (Th17)/regulatory T (Treg) cell balance in food allergy (FA). Methods Active components, action targets of JWYGS, and FA-related targets, were screened via network pharmacology. Overlapping targets between JWYGS and FA were used to construct a protein-protein interaction (PPI) network. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses were performed to predict key signaling pathways. Molecular docking was conducted to validate the binding affinity between the main active components and the predicted targets. Mice were randomly divided into control group, model group, JWYGS low-dose, medium-dose, and high-dose groups, and dexamethasone (DXM) group. An ovalbumin (OVA)-induced FA model was established. During the OVA challenge period, mice received daily intragastric administration, after which allergy and diarrhea scores were assessed. Small intestinal pathology was evaluated by HE staining. Serum ovalbumin-specific immunoglobulin E (OVA-sIgE), interleukin 6 (IL-6), IL-17, IL-2, and IL-10 were measured by ELISA. Small intestinal IL-6, IL-17, and IL-10 protein expression was detected by immunohistochemistry. Splenic Th17 and Treg cells were quantified by flow cytometry, and the Th17/Treg ratio was calculated. The mRNA expression of IL-6, retinoic acid receptor-related orphan receptor γt (RORγt), and forkhead box protein P3 (FOXP3) in the small intestine was detected by qPCR. Results Network pharmacology identified 235 active components of JWYGS and 136 common targets. GO and KEGG enrichment analyses highlighted cytokine response and Th17 differentiation. Molecular docking confirmed stable binding between core components and targets. Compared with the control group, the model group exhibited aggravated allergy and diarrhea scores, marked small intestinal inflammation and mucosal damage, elevated serum levels of OVA-sIgE, IL-6, IL-17 and IL-2, along with increased splenic Th17 cell frequency and Th17/Treg ratio. Intestinal IL-6 and IL-17 protein levels as well as IL-6 and RORγt mRNA expression were upregulated, whereas serum IL-10 levels were decreased, and intestinal expression of IL-10 protein and FOXP3 mRNA was downregulated. After JWYGS treatment, allergy and diarrhea scores were significantly reduced. Small intestinal inflammation and mucosal damage were alleviated. Serum levels of OVA-sIgE, IL-17, IL-6 and IL-2, Th17 cell frequency and the Th17/Treg ratio, intestinal IL-6 and IL-17 protein levels were decreased. IL-6 and RORγt mRNA expression was downregulated. Serum IL-10 levels were increased and intestinal expression of IL-10 protein and FOXP3 mRNA was upregulated. Moreover, the JWYGS high-dose group demonstrated comparable efficacy to the DXM group. Conclusion JWYGS can ameliorate symptoms and reverse the Th17/Treg imbalance in FA mice, potentially by inhibiting IL-6 transcription and regulating RORγt/FOXP3 expression.

Animals↗

PubMed1999

Eleven novel sep genes of Schizosaccharomyces pombe required for efficient cell separation and sexual differentiation.

Genetic analysis of 20 sterile mutants prone to form hyphae revealed 11 novel ste genes (sep6 to sep16) of Schizosaccharomyces pombe. None of the mutants was completely mycelial. Most mutants formed branching hyphae and showed normal septation. Aberrant septal structures and actin distribution were seen only at 36 degrees C. sep9-307, sep14-576 and sep15-598 showed genetic interactions with sep1-1, a mutation in a forkhead transcription factor homologue. Additional genetic interactions were detected between sep6-194, sep15-598 and cdc16-116, a mutant allele of an anaphase modulator of p34cdc2. sep9-307 and sep15-598 caused dikaryosis in wee1- background. In mating and sporulation tests, sep6-, sep7-, sep9-, sep10-, sep11- and sep15- proved to be defective in conjugation only, whereas sep8-, sep13- and sep16- were also defective in meiosis-sporulation. sep12- and sep14- were only partially sterile. All mutants could produce M-factor but sep8-, sep11-, sep15- and sep16- were defective in P-factor production. The mutations in sep8, sep11 and sep16 suppressed the pat1-114-driven meiosis. All mutants were sensitive to the presence of higher concentrations of chloride in the medium and to short heat shocks. The diversity of the mutant phenotypes and the pleiotropic effects of the mutations suggest that these sep genes might act in, or interact with, a multiple overlapping network of regulatory modules.

Actins↗

PubMed1998

Expression of hepatocyte nuclear factor-3alpha in rat prostate, seminal vesicle, and bladder.

Hepatocyte nuclear factor-3alpha (HNF-3alpha), a member of the hepatocyte-forkhead-homolog family of transcription factors, regulates gene expression in the endoderm-derived liver and lung. To determine if HNF-3alpha might also play a role in endodermal derivatives of the urogenital sinus, the expression of HNF-3alpha in male accessory sex organs was assessed by Northern blotting, in situ hybridization, and electrophoretic mobility shift analysis. RNA from the dorsolateral prostate (DP), ventral prostate (VP), anterior prostate (AP), seminal vesicle (SV), and bladder was compared with RNA from the liver and spleen as positive and negative controls, respectively. HNF-3alpha mRNA levels in the DP, VP, AP, and bladder were 20, 14, 5, and 6 times higher than the SV equivalent in the liver. HNF-3alpha mRNA was detected in 8 of 10 prostate epithelial cell lines (rat NRP 152 and 154, mouse Pr14, and human DU-145, PC3, LNCaP, ND-1, and BPH-1) but not in rat Dunning epithelial or mouse Pr12 cells. Addition of testosterone to castrated rats was found to prevent a drastic loss of HNF-3alpha mRNA in the VP. This result suggests that HNF-3alpha mRNA levels are at least indirectly regulated by testosterone. The HNF-3alpha mRNA is expressed in epithelial cells of the urogenital sinus derivatives VP, AP, DP, and bladder and Wolffian duct derivative, the SV. To confirm that functional HNF-3alpha protein is produced in the VP, electrophoretic mobility shift assays were performed with whole-cell extracts and high-affinity oligonucleotide (TTR-S) from the transthyretin promoter. Binding to TTR-S was disrupted when the extract was incubated with HNF-3alpha, but not with HNF-3beta, antibody. Taken together, the results using VP, AP, DP, SV, and bladder suggest that HNF-3alpha may play an important role in development and maintenance of urogenital tract epithelial cells.

Amino Acid Sequence↗