Forkhead box protein A2 (FOXA2) protein stability and activity are regulated by sumoylation.

The forkhead box protein A2 (FOXA2) is an important regulator of glucose and lipid metabolism and organismal energy balance. Little is known about how FOXA2 protein expression and activity are regulated by post-translational modifications. We have identified that FOXA2 is post-translationally modified by covalent attachment of a small ubiquitin related modifier-1 (SUMO-1) and mapped the sumoylation site to the amino acid lysine 6 (K6).

PIAS1 is a GATA4 SUMO ligase that regulates GATA4-dependent intestinal promoters independent of SUMO ligase activity and GATA4 sumoylation.

GATA4 confers cell type-specific gene expression on genes expressed in cardiovascular, gastro-intestinal, endocrine and neuronal tissues by interacting with various ubiquitous and cell-type-restricted transcriptional regulators. By using yeast two-hybrid screening approach, we have identified PIAS1 as an intestine-expressed GATA4 interacting protein. The physical interaction between GATA4 and PIAS1 was confirmed in mammalian cells by coimmunoprecipitation and two-hybrid analysis.

Serum response factor expression is enriched in pancreatic β cells and regulates insulin gene expression.

Serum response factor (SRF) is an essential regulator of myogenic and neurogenic genes and the ubiquitously expressed immediate-early genes. The purpose of this study is to determine SRF expression pattern in murine pancreas and examine the role of SRF in pancreatic gene expression. Immunohistochemical analysis of wild-type pancreas and LacZ staining of pancreas from SRF LacZ knock-in animals showed that SRF expression is restricted to β cells.

GATA factors in gastrointestinal malignancy.

GATA factors are unique transcription factors with conserved DNA-binding domains. They serve diverse roles in embryogenesis, cell differentiation, regulation of tissue-specific genes, and carcinogenesis. The subfamily GATA-4, -5, and -6 are highly expressed in endoderm-derived organs and regulate multiple gut-specific genes.

GATA6 promotes colon cancer cell invasion by regulating urokinase plasminogen activator gene expression.

GATA6 is a zinc finger transcription factor expressed in the colorectal epithelium. We have examined the expression of GATA6 in colon cancers and investigated the mechanisms by which GATA6 regulates colon cancer cell invasion. GATA6 was overexpressed in colorectal polyps and primary and metastatic tumors.

Histone deacetylase 7 and FoxA1 in estrogen-mediated repression of RPRM.

Activation of estrogen receptor alpha (ERalpha) results in both induction and repression of gene transcription; while mechanistic details of estrogen induction are well described, details of repression remain largely unknown. We characterized several ERalpha-repressed targets and examined in detail the mechanism for estrogen repression of Reprimo (RPRM), a cell cycle inhibitor. Estrogen repression of RPRM is rapid and robust and requires a tripartite interaction between ERalpha, histone deacetylase 7 (HDAC7), and FoxA1.

PDX-1 acts as a potential molecular target for treatment of human pancreatic cancer.

Objectives: The purpose of this study was to investigate whether pancreatic and duodenal homeobox factor 1 (PDX-1) could serve as a potential molecular target for the treatment of pancreatic cancer.

Methods: Cell proliferation, invasion capacity, and protein levels of cell cycle mediators were determined in human pancreatic cancer cells transfected with mouse PDX-1 (mPDX-1) alone or with mPDX-1 short hairpin RNA (shRNA) and/or human PDX-1 shRNA (huPDX-1 shRNA). Tumor cell growth and apoptosis were also evaluated in vivo in PANC-1 tumor-bearing severe combined immunodeficient mice receiving multiple treatments of intravenous liposomal huPDX-1 shRNA.

PDX-1 expression is associated with islet proliferation in vitro and in vivo.

Background: Transcription factor pancreatic duodenal homeobox-1 (PDX-1) is critical for beta-cell differentiation and insulin gene expression. In this study, we investigated the role of PDX-1 in ductal-to-islet cell transdifferentiation, islet cell apoptosis, and proliferation in addition to other regulators associated with these processes in two developing beta-cell models.

Materials And Methods: CAPAN-1 cells were cultured with the GLP-1 analogue Exendin-4 (Ex-4) to induce transdifferentiation to an insulin-producing phenotype.

Cooperation between GATA4 and TGF-beta signaling regulates intestinal epithelial gene expression.

Members of the transforming growth factor-beta (TGF-beta) family have been shown to play an important role in the regulation of gut epithelial gene expression. We have used the intestinal alkaline phosphatase (IAP) and intestinal fatty acid binding protein (IFABP) promoters to dissect the mechanisms by which TGF-beta1 signaling regulates gut epithelial gene expression. TGF-beta signaling alone was not sufficient for activation of IAP and IFABP promoters.

LIM-only protein, CRP2, switched on smooth muscle gene activity in adult cardiac myocytes.

Smooth muscle alpha-actin gene activity appears in promyocardial cells well before cardiac myocyte differentiation and is down-regulated during the onset of rhythmic contractility and cardiac morphogenesis. The levels of LIM-only CRP2 correlated well with smooth muscle gene activity. Cardiomyocyte-specific expression of CRP2 in transgenic mice showed robust expression of smooth muscle cell-specific transcripts and protein filaments in the adult heart.

Conditional mutagenesis of the murine serum response factor gene blocks cardiogenesis and the transcription of downstream gene targets.

Serum response factor (SRF) homozygous-null embryos from our backcross of SRF(LacZ/)(+) "knock-in" mice failed to gastrulate and form mesoderm, similar to the findings of an earlier study (Arsenian, S., Weinhold, B., Oelgeschlager, M.

Recruitment of the androgen receptor via serum response factor facilitates expression of a myogenic gene.

Androgen receptor (AR) induced precocious myogenesis in culture and myogenic specified gene activity. Increased levels of AR expression in replicating C2C12 myoblasts stimulated fusion into post-differentiated multinucleated myotubes and the appearance of skeletal alpha-actin transcripts, even in the absence of ligand. Furthermore, AR activated the skeletal alpha-actin promoter, which lacks GRE sites, in co-transfected C2C12 cells.

Serum response factor, an enriched cardiac mesoderm obligatory factor, is a downstream gene target for Tbx genes.

We tested the idea that T-box factors direct serum response factor (SRF) gene activity early in development. Analysis of SRF-LacZ "knock-in" mice showed highly restricted expression in early embryonic cardiac and skeletal muscle mesoderm and neuroectoderm. Examination of the SRF gene for regulatory regions by linking the promoter and 5'-flanking sequences, up to 5.

Serum response factor is alternatively spliced in human colon cancer.

Background: Serum response factor (SRF) is a transcription factor that plays an important role in cellular differentiation and cell cycle regulation. SRF function is regulated in part by alternative splicing. Little is known about the expression or role of these alternatively spliced isoforms during tumorigenesis.

Cysteine-rich LIM-only proteins CRP1 and CRP2 are potent smooth muscle differentiation cofactors.

Cysteine-rich LIM-only proteins, CRP1 and CRP2, expressed during cardiovascular development act as bridging molecules that associate with serum response factor and GATA proteins. SRF-CRP-GATA complexes strongly activated smooth muscle gene targets. CRP2 was found in the nucleus during early stages of coronary smooth muscle differentiation from proepicardial cells.

Developmental expression of serum response factor in the rat central nervous system.

Serum response factor (SRF), a transcription factor known to be essential for early embryonic development as well as post-natal regulation of both cellular proliferation and myogenic differentiation, is expressed broadly in neurons within the adult mammalian central nervous system (CNS). The function of SRF within the developing CNS is not well established, but it is likely to play an important role in neuraxial development and neuronal function, since many of its known target genes (e.g.

Transforming growth factor-beta induction of smooth muscle cell phenotpye requires transcriptional and post-transcriptional control of serum response factor.

Transforming growth factor-beta induces a smooth muscle cell phenotype in undifferentiated mesenchymal cells. To elucidate the mechanism(s) of this phenotypic induction, we focused on the molecular regulation of smooth muscle-gamma-actin, whose expression is induced at late stages of smooth muscle differentiation and developmentally restricted to this lineage. Transforming growth factor-beta induced smooth muscle-gamma-actin protein, cytoskeletal localization, and mRNA expression in mesenchymal cells.