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Padma-sheela Jayaraman - One of the best experts on this subject based on the ideXlab platform.

  • urokinase type plasminogen activator upa promotes angiogenesis by attenuating proline rich Homeodomain Protein prh transcription factor activity and de repressing vascular endothelial growth factor vegf receptor expression
    Journal of Biological Chemistry, 2016
    Co-Authors: Victoria Stepanova, Padma-sheela Jayaraman, Sergei Zaitsev, Tatiana Lebedeva, Khalil Bdeir, Rachael M Kershaw, Kelci R Holman, Yelena V Parfyonova, E V Semina, I B Beloglazova
    Abstract:

    Urokinase-type plasminogen activator (uPA) regulates angiogenesis and vascular permeability through proteolytic degradation of extracellular matrix and intracellular signaling initiated upon its binding to uPAR/CD87 and other cell surface receptors. Here, we describe an additional mechanism by which uPA regulates angiogenesis. Ex vivo VEGF-induced vascular sprouting from Matrigel-embedded aortic rings isolated from uPA knock-out (uPA(-/-)) mice was impaired compared with vessels emanating from wild-type mice. Endothelial cells isolated from uPA(-/-) mice show less proliferation and migration in response to VEGF than their wild type counterparts or uPA(-/-) endothelial cells in which expression of wild type uPA had been restored. We reported previously that uPA is transported from cell surface receptors to nuclei through a mechanism that requires its kringle domain. Intranuclear uPA modulates gene transcription by binding to a subset of transcription factors. Here we report that wild type single-chain uPA, but not uPA variants incapable of nuclear transport, increases the expression of cell surface VEGF receptor 1 (VEGFR1) and VEGF receptor 2 (VEGFR2) by translocating to the nuclei of ECs. Intranuclear single-chain uPA binds directly to and interferes with the function of the transcription factor hematopoietically expressed Homeodomain Protein or proline-rich Homeodomain Protein (HHEX/PRH), which thereby lose their physiologic capacity to repress the activity of vehgr1 and vegfr2 gene promoters. These studies identify uPA-dependent de-repression of vegfr1 and vegfr2 gene transcription through binding to HHEX/PRH as a novel mechanism by which uPA mediates the pro-angiogenic effects of VEGF and identifies a potential new target for control of pathologic angiogenesis.

  • the proline rich Homeodomain Protein recruits members of the groucho transducin like enhancer of split Protein family to co repress transcription in hematopoietic cells
    Journal of Biological Chemistry, 2004
    Co-Authors: Tracey E Swingler, Kirstin L Bess, Jing Yao, Stefano Stifani, Padma-sheela Jayaraman
    Abstract:

    Abstract The proline-rich Homeodomain Protein (PRH/Hex) is important in the control of cell proliferation and differentiation and in the regulation of multiple processes in embryonic development. We have shown previously that PRH contains two domains that can independently bring about transcriptional repression. The PRH Homeodomain represses transcription by binding to TATA box sequences, whereas the proline-rich N-terminal domain of PRH can repress transcription when attached to a heterologous DNA-binding domain. The Groucho/transducin-like enhancer of split (TLE) family of Proteins are transcriptional co-repressors that interact with a number of DNA-bound transcription factors and play multiple roles in development. Here we demonstrate that the proline-rich N-terminal domain of PRH binds to TLE1 in vitro and in yeast two-hybrid assays. We show that PRH and TLE Proteins are co-expressed in hematopoietic cells and interact in co-immunoprecipitation assays. We demonstrate that TLE1 increases repression by PRH in transient transfection assays and that titration of endogenous TLE Proteins by co-expression of Grg5, a natural trans-dominant negative Protein, alleviates transcriptional repression by PRH. Finally, we show that a mutation in the PRH N-terminal domain that blocks the PRH-TLE1 interaction in vitro eliminates co-repression. We discuss these results in terms of the roles of PRH and TLE in cell differentiation and development.

  • Purification of the proline-rich Homeodomain Protein.
    Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2003
    Co-Authors: Amy J Butcher, Kevin Gaston, Padma-sheela Jayaraman
    Abstract:

    The proline-rich Homeodomain Protein (PRH), also known as Hex, is a transcriptional repressor expressed in a variety of cell types. The PRH Protein contains a proline-rich N-terminal domain that can repress transcription when attached to a heterologous DNA binding domain, a central Homeodomain that mediates sequence-specific DNA binding, and an acidic C-terminal domain of unknown function. Although individual domains of PRH have been expressed in bacterial cells as GST- and histidine-tagged fusion Proteins, attempts to express and purify the full-length Protein have met with little success. Here we describe the purification of a histidine-tagged full-length PRH fusion Protein. The Protein described here will allow us to determine the mechanisms whereby PRH represses transcription.

  • The Homeodomain Protein PRH influences the differentiation of haematopoietic cells
    Leukemia research, 2000
    Co-Authors: Padma-sheela Jayaraman, Jonathan Frampton, Graham H. Goodwin
    Abstract:

    Haematopoiesis involves the differentiation of a self-renewing stem cell into all of the lineages found in circulating blood. Myb-Ets transformed chicken blastoderm cells (MEPs) have many of the characteristics of multipotent haematopoietic cells and represent a useful model system for the study of haematopoiesis. The proline-rich Homeodomain Protein (PRH) has previously been shown to be expressed in the haematopoietic compartment. In this report we show that PRH mRNA and Protein levels are down regulated as MEPs differentiate along the myelomonocytic and erythrocytic lineages. In contrast, PRH mRNA and Protein levels remain high as MEPs differentiate toward the thrombocytic lineage. Over-expression of full length PRH in MEPs inhibits their transformation and/or proliferation. However, the over-expression of N-terminally truncated PRH Proteins results in normally proliferating cells that are predominantly differentiated along the myelomonocytic and eosinophilic lineages. These results suggest that PRH plays a role in the proliferation and differentiation of haematopoietic cells.

Gary Struhl - One of the best experts on this subject based on the ideXlab platform.

  • rna recognition and translational regulation by a Homeodomain Protein
    Nature, 1996
    Co-Authors: Josh Dubnau, Gary Struhl
    Abstract:

    In Drosophila, the primary determinant of anterior pattern is the gradient morphogen bicoid (bed), a Homeodomain Protein that binds DMA and transcriptionally activates target genes at different threshold concentrations. Here we present evidence that bed also binds RNA and acts as a translational represser to generate an opposing gradient of the Homeodomain Protein caudal (cad). RNA binding by bed seems to involve direct interactions between the bed Homeodomain and discrete target sequences within the 3′ untranslated region of the cad messenger RNA and to block the initiation of cad translation.

  • RNA recognition and translational regulation by a Homeodomain Protein
    Nature, 1996
    Co-Authors: Josh Dubnau, Gary Struhl
    Abstract:

    In Drosophila, the primary determinant of anterior pattern is the gradient morphogen bicoid (bcd), a Homeodomain Protein that binds DNA and transcriptionally activates target genes at different threshold concentrations. Here we present evidence that bcd also binds RNA and acts as a translational repressor to generate an opposing gradient of the Homeodomain Protein caudal (cad). RNA binding by bcd seems to involve direct interactions between the bcd Homeodomain and discrete target sequences within the 3' untranslated region of the cad messenger RNA and to block the initiation of cad translation.

Joel F. Habener - One of the best experts on this subject based on the ideXlab platform.

  • the Homeodomain Protein idx 1 increases after an early burst of proliferation during pancreatic regeneration
    Diabetes, 1999
    Co-Authors: Amitabh Sharma, Christopher Miller, Joel F. Habener, David Zangen, P Reitz, Monica Taneja, Matthew E Lissauer, Gordon C Weir, Susan Bonnerweir
    Abstract:

    Islet duodenal homeobox 1 (IDX-1/PF-1/STF-1/PDX-1), a Homeodomain Protein that transactivates the insulin promoter, has been shown by targeted gene ablation to be required for pancreatic development. After 90% pancreatectomy (Px), the adult pancreas regenerates in a process recapitulating embryonic development, starting with a burst of proliferation in the epithelium of the common pancreatic duct. In this model, IDX-1 mRNA was detected by semiquantitative reverse transcription-polymerase chain reaction in total RNA from isolated common pancreatic ducts at levels 10% of those of isolated islets. The IDX-1 mRNA levels were not significantly different for common pancreatic ducts of Px, sham Px, and unoperated rats and did not change with time after surgery. By immunoblot analysis, IDX-1 Protein was only faintly detected in these ducts 1 and 7 days after Px or sham Px but was easily detected at 2 and 3 days after Px. Similarly, IDX-1 immunostaining was barely detectable in sham or unoperated ducts but was strong in ducts at 2-3 days after Px. The increase of IDX-1 immunostaining followed that of BrdU incorporation (proliferation). These results indicate a posttranscriptional regulation of the IDX-1 expression in ducts. In addition, islets isolated 3-7 d after Px showed higher IDX-1 Protein expression than control islets. Thus, in pancreatic regeneration IDX-1 is upregulated in newly divided ductal cells as well as in islets. The timing of enhanced expression of IDX-1 implies that IDX-1 is not important in the initiation of regeneration but may be involved in the differentiation of ductal cells to beta-cells.

  • Misexpression of the pancreatic Homeodomain Protein IDX-1 by the Hoxa-4 promoter associated with agenesis of the cecum
    Gastroenterology, 1998
    Co-Authors: R. Scott Heller, Doris A. Stoffers, Mehboob A. Hussain, Christopher Miller, Joel F. Habener
    Abstract:

    Abstract Background & Aims: The endoderm-specific Homeodomain transcription factor IDX-1 is critical for pancreas development and for the regulation of islet cell–specific genes. During development, IDX-1 is expressed in the epithelial cells of the endoderm in the pancreatic anlage of the foregut. The aim of this study was to determine whether IDX-1 may have potential properties of a master homeotic determinant of pancreas and/or gut development. Methods: Transgenic mice were generated in which the expression of IDX-1 was misdirected by a promoter of the mesoderm-specific Homeodomain Protein Hoxa-4 known to express in the stomach and hindgut during development. The expectation was the formation of ectopic pancreatic tissue or alterations of gut patterning or morphology. Results: Although no ectopic induction of pancreatic markers was found in these transgenic mice, they manifested an altered midgut-hindgut union and agenesis of the cecum. Further, IDX-1 binds to the gut-specific Homeodomain Protein Cdx-2 and inhibits transactivation of the sucrase-isomaltase promoter by Cdx-2. Conclusions: These findings further support the emerging understanding that interactions among different classes of Homeodomain Proteins, expressed in a spatially and temporally restricted manner during development, determine the pattern of organogenesis. A possible mechanism for the dysmorphogenesis of the proximal colon may be an inhibition of Cdx-2 actions by IDX-1. GASTROENTEROLOGY 1998;115:381-387

Robert H Horvitz - One of the best experts on this subject based on the ideXlab platform.

  • coordinated transcriptional regulation of the unc 25 glutamic acid decarboxylase and the unc 47 gaba vesicular transporter by the caenorhabditis elegans unc 30 Homeodomain Protein
    The Journal of Neuroscience, 1999
    Co-Authors: Catharine Eastman, Yishi Jin, Robert H Horvitz
    Abstract:

    An important aspect of the specification of neuronal fate is the choice of neurotransmitter. In Caenorhabditis elegans the neurotransmitter GABA is synthesized by the UNC-25 glutamic acid decarboxylase (GAD) and packaged into synaptic vesicles by the UNC-47 transporter. Both unc-25 and unc-47 are expressed in 26 GABAergic neurons of five different types. Previously, we have identified that the unc-30 homeobox gene controls the fate of 19 type D GABAergic neurons. We report here that the UNC-30 Homeodomain Protein transcriptionally regulates the expression of unc-25 and unc-47 in the 19 type D neurons. UNC-30 bound to the unc-25 and unc-47 promoters sequence-specifically. Mutations in the UNC-30 binding sites of the unc-25 and unc-47 promoters abolished the expression of reporter genes in the D neurons. The ectopic expression of UNC-30 induced the ectopic expression of reporter genes driven by the wild-type unc-25 and unc-47 promoters. Our data establish a mechanism for cell type-specific transcriptional coregulation of genes required for the synthesis and packaging of the neurotransmitter GABA.

  • control of type d gabaergic neuron differentiation by c elegans unc 30 Homeodomain Protein
    Nature, 1994
    Co-Authors: Yishi Jin, Roger Hoskins, Robert H Horvitz
    Abstract:

    THE Caenorhabditis elegans gene unc-30 is required for the develop-ment and functioning of the 19 inhibitory GABAergic (γ-aminobutyric-acid-secreting) type D motor neurons, which control locomotion1–4. In unc-30 mutants the D neurons lack GAB A2 and have defects in axonal pathfinding and synaptic connections (J. White, personal communication). We report here that unc-30 encodes a Homeodomain Protein that is present in the nuclei of the D neurons at high levels in young larvae, in which the motor cir-cuitry is formed, and at low levels in older animals. The UNC-30 Protein is also present in six non-G A B Aergic neurons and is absent from the seven non-D-type GABAergic neurons. Ectopic expres-sion of unc-30 induced GABA expression in cells that are normally not GABAergic. We propose that unc-30 functions as a transcrip-tional regulator within the type D neurons to control their terminal differentiation and that unc-30 is sufficient in some but not all cell types to induce GABA expression.

Yishi Jin - One of the best experts on this subject based on the ideXlab platform.

  • coordinated transcriptional regulation of the unc 25 glutamic acid decarboxylase and the unc 47 gaba vesicular transporter by the caenorhabditis elegans unc 30 Homeodomain Protein
    The Journal of Neuroscience, 1999
    Co-Authors: Catharine Eastman, Yishi Jin, Robert H Horvitz
    Abstract:

    An important aspect of the specification of neuronal fate is the choice of neurotransmitter. In Caenorhabditis elegans the neurotransmitter GABA is synthesized by the UNC-25 glutamic acid decarboxylase (GAD) and packaged into synaptic vesicles by the UNC-47 transporter. Both unc-25 and unc-47 are expressed in 26 GABAergic neurons of five different types. Previously, we have identified that the unc-30 homeobox gene controls the fate of 19 type D GABAergic neurons. We report here that the UNC-30 Homeodomain Protein transcriptionally regulates the expression of unc-25 and unc-47 in the 19 type D neurons. UNC-30 bound to the unc-25 and unc-47 promoters sequence-specifically. Mutations in the UNC-30 binding sites of the unc-25 and unc-47 promoters abolished the expression of reporter genes in the D neurons. The ectopic expression of UNC-30 induced the ectopic expression of reporter genes driven by the wild-type unc-25 and unc-47 promoters. Our data establish a mechanism for cell type-specific transcriptional coregulation of genes required for the synthesis and packaging of the neurotransmitter GABA.

  • control of type d gabaergic neuron differentiation by c elegans unc 30 Homeodomain Protein
    Nature, 1994
    Co-Authors: Yishi Jin, Roger Hoskins, Robert H Horvitz
    Abstract:

    THE Caenorhabditis elegans gene unc-30 is required for the develop-ment and functioning of the 19 inhibitory GABAergic (γ-aminobutyric-acid-secreting) type D motor neurons, which control locomotion1–4. In unc-30 mutants the D neurons lack GAB A2 and have defects in axonal pathfinding and synaptic connections (J. White, personal communication). We report here that unc-30 encodes a Homeodomain Protein that is present in the nuclei of the D neurons at high levels in young larvae, in which the motor cir-cuitry is formed, and at low levels in older animals. The UNC-30 Protein is also present in six non-G A B Aergic neurons and is absent from the seven non-D-type GABAergic neurons. Ectopic expres-sion of unc-30 induced GABA expression in cells that are normally not GABAergic. We propose that unc-30 functions as a transcrip-tional regulator within the type D neurons to control their terminal differentiation and that unc-30 is sufficient in some but not all cell types to induce GABA expression.