Regina Raz - Academia.edu (original) (raw)

Papers by Regina Raz

Research paper thumbnail of Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors

Journal of Biological Chemistry

Research paper thumbnail of Human antibodies to human RANKL, encoding nucleic acids and methods of treatment

Research paper thumbnail of Structural abnormalities associated with congenital megacolon in transgenic mice that overexpress theHoxa-4 gene

American Journal of Anatomy, 1993

Congenital megacolon develops in transgenic mice that overexpress the homeobox-containing gene, H... more Congenital megacolon develops in transgenic mice that overexpress the homeobox-containing gene, Hoxu-4. The current study was done to identify abnormalities of the terminal colon that might account for the phenotype. The terminal bowel of transgenic mice was compared with that of control and lethal spotted (ZslZs) mice, a strain in which megacolon also develops. The terminal colon of the transgenic mice 0 1993 WILEY-LISS, INC. that found in ZslZs mice. These data suggest that both smooth muscle and the innervation of the terminal bowel of neonatal Hoxu-4 transgenic mice are structurally abnormal. Although some of the abnormalities seen in Hoxu-4 transgenic mice are similar to those which arise in Zslls mice, the two conditions are not identical. In both animals, the data are consistent with the hypothesis that the defects arise as a result of a defective interaction between the precursors of enteric neurons and smooth muscle. o 1993 Wiley-Liss, Inc.

Research paper thumbnail of Análisis de un gen de pared celular y de una familia de secuencias moderadamente repetidas en los géneros "Zea" y "Sorghum" de Graminae: implicaciones evolutivas y funcionales

Research paper thumbnail of Cytoplasmic transcription factors: mediators of cytokine signaling

Agents and Actions Supplements, Feb 1, 1995

The distinct pattern of transcriptional responses of cells to different extracellular signals req... more The distinct pattern of transcriptional responses of cells to different extracellular signals requires a signal transduction pathway that provides rapid, accurate, and faithful transmission of information from the cell surface to the nucleus. One mechanism exploited by many cytokines, exemplified by interferons (IFN) but also used by many interleukins and growth factors, uses a family of cytoplasmic transcription factors that are activated by tyrosine phosphorylation. Once phosphorylated by receptor-associated tyrosine kinases, these proteins assemble into multimeric transcription factors, translocate to the nucleus, and bind specific DNA sequence elements in the promoters of target genes.

Research paper thumbnail of Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target

Nature Medicine, Jun 1, 2005

Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose t... more Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma.

Research paper thumbnail of STAT1 mediates the increased apoptosis and reduced chondrocyte proliferation in mice overexpressing FGF2

Development (Cambridge, England), 2001

Unregulated FGF receptor signaling results in bone malformations that affect both endochondral an... more Unregulated FGF receptor signaling results in bone malformations that affect both endochondral and intramembranous ossification, and is the basis for several genetic forms of human dwarfism. FGF signaling inhibits chondrocyte proliferation and we have previously shown that the transcription factor STAT1 mediates the growth inhibitory effect of FGF in vitro. We provide genetic evidence that STAT1 is a modulator of the negative regulation of bone growth by FGF in vivo. We crossed Stat1(-/-) mice with a transgenic mouse line overexpressing human FGF2 (TgFGF). TgFGF mice exhibit phenotypes characterized by chondrodysplasia and macrocephaly, which affect endochondral and intramembranous ossification. We found that the chondrodysplasic phenotype of these mice results both from reduced proliferation and increased apoptosis of growth plate chondrocytes. Loss of STAT1 function in TgFGF mice led to a significant correction of the chondrodysplasic phenotype, but did not affect the skull malfor...

Research paper thumbnail of Structure-Function Analysis of ISGF3 Complex-Formation

Research paper thumbnail of Mechanisms of resistance to pathogen infections mediated by interferons signaling through the jak-Stat pathway

Research paper thumbnail of Genome-wide generation of knock-out mice and in vivo expression profiling using VelocigeneTM, a new high-throughput method, identifies novel genes expressed in bone and cartilage

Research paper thumbnail of Ror2 (W749X), a mutation carried by brachydactyly B patients, causes brachydactyly in the mouse and altered early cartilage development

Research paper thumbnail of Bmp3-Null Aged Mice Display Increased Trabecular Bone Volume and Reduced Cross Sectional Area at the Mid-Femoral Diaphysis

Research paper thumbnail of Stat3 and Ras activation are required for the cellular transformation mediated by NPM-ALK

Research paper thumbnail of A conditional null allele for the BMP antagonist noggin using a novel method for generating conditional knock-out mice

Research paper thumbnail of Cytoplasmic Transcription Factors: Mediators of Cytokine Signaling

Inflammation: Mechanisms and Therapeutics, 1995

The distinct pattern of transcriptional responses of cells to different extracellular signals req... more The distinct pattern of transcriptional responses of cells to different extracellular signals requires a signal transduction pathway that provides rapid, accurate, and faithful transmission of information from the cell surface to the nucleus. One mechanism exploited by many cytokines, exemplified by interferons (IFN) but also used by many interleukins and growth factors, uses a family of cytoplasmic transcription factors that are activated by tyrosine phosphorylation. Once phosphorylated by receptor-associated tyrosine kinases, these proteins assemble into multimeric transcription factors, translocate to the nucleus, and bind specific DNA sequence elements in the promoters of target genes.

Research paper thumbnail of The sequence of a hydroxyproline-rich glycoprotein gene from Sorghum vulgare

Plant Molecular Biology, 1991

Research paper thumbnail of Chromosome localization and characterization of a family of long interspersed repetitive DNA elements from the genus Zea

Theoretical and Applied Genetics, 1995

This paper describes the characterization and chromosomal distribution of new long repetitive seq... more This paper describes the characterization and chromosomal distribution of new long repetitive sequences present in all species of the genus Zea. These sequences constitute a family of moderately repetitive elements ranging approximately from 1350 to 1700 copies per haploid genome in modern maize (Zea mays ssp. mays) and teosinte (Zea diploperennis), respectively. The elements are long, probably larger than 9 kb, and they show a highly conserved internal organization among Zea subspecies and species. The elements are present in all maize chromosomes in an interspersed pattern of distribution, are absent from centromeric and pericentric heterochromatin, and with some clustering in the distal regions of chromosome arms.

Research paper thumbnail of Expression of a Maize Cell Wall Hydroxyproline-Rich Glycoprotein Gene in Early Leaf and Root Vascular Differentiation

THE PLANT CELL ONLINE, 1990

The spatial pattern of expression for a maize gene encoding a hydroxyproline-rich glycoprotein (H... more The spatial pattern of expression for a maize gene encoding a hydroxyproline-rich glycoprotein (HRGP) was determined by in situ hybridization. During normal development of roots and leaves, the expression of the gene was transient and particularly high in regions initiating vascular elements and associated sclerenchyma. Its expression was also associated with the differentiation of vascular elements in a variety of other tissues. The gene encoded an HRGP that had been extracted from the cell walls of maize suspension culture cells and several other embryonic and post-embryonic tissues. The gene was present in one or two copies in different varieties of maize and in the related monocots teosinte and sorghum. A single gene was cloned from maize using a previously characterized HRGP cDNA clone [Stiefel et al. (1988). Plant MOI. Biol. 11, 483-4931. In addition to the coding sequences for the HRGP and an N-terminal signal sequence, the gene contained a single intron in the nontranslated 3' end.

Research paper thumbnail of Three distinct loci on human chromosome 21 contribute to interferon-α/β responsiveness

Somatic Cell and Molecular Genetics, 1995

The species specificity of interferons (IFNs) depends on restricted recognition of these ligands ... more The species specificity of interferons (IFNs) depends on restricted recognition of these ligands by multisubunit cell surface receptors. Expression of the human receptor subunit IFNAR in mouse cells conferred sensitivity only to one subtype of human IFN, IFN-od3. Other genes on human chromosome 21 were required for responses to other subtypes of type I IFN. In contrast, IFNAR expression in hamster cells did not confer sensitivity to any human IFN tested, including IFN-ed3. Using human-hamster somatic cell hybrids, we mapped the Ifnabr gene, encoding a ligand-binding subunit of the IFN-ot/[3 (type I) receptor, to human chromosome 21. Ifnabr colocalized with Ifnar to the distal region of q22.1. The presence of a chromosomal fragment encoding IFNABR and IFNAR was also not sufficient to confer sensitivity to human IFN. In contrast, hybrids carrying in addition the region 21q22.2 showed a full response to human IFN-od3, suggesting that a gene located in this region encodes a third factor required for type I IFN receptor activity.

Research paper thumbnail of Essential role of STAT3 for embryonic stem cell pluripotency

Proceedings of the National Academy of Sciences, 1999

Propagation of mouse embryonic stem (ES) cells in vitro requires exogenous leukemia inhibitory fa... more Propagation of mouse embryonic stem (ES) cells in vitro requires exogenous leukemia inhibitory factor (LIF) or related cytokines. Potential downstream effectors of the LIF signal in ES cells include kinases of the Src, Jak, and mitogen-activated protein families and the signal transducer and transcriptional activator STAT3. Activation of nuclear STAT3 and the ability of ES cells to grow as undifferentiated clones were monitored during LIF withdrawal. A correlation was found between levels of STAT3 activity and maintenance of an undifferentiated phenotype at clonal density. In contrast, variation in STAT3 activity did not affect cell proliferation. The requirement for STAT3 was analyzed by targeted mutagenesis in ES cell lines exhibiting different degrees of LIF dependency. An insertional mutation was devised that abrogated Stat3 gene expression but could be reversed by Cre recombination-mediated excision. ES cells heterozygous for the Stat3 mutation could be isolated only from E14 cells, the line least dependent on LIF for self-renewal. Targeted clones isolated from other ES cell lines were invariably trisomic for chromosome 11, which carries the Stat3 locus, and retained normal levels of activated STAT3. Cre-regulated reduction of Stat3 gene copy number in targeted, euploid E14 clones resulted in dose-dependent losses of STAT3 activity and the efficiency of self-renewal without commensurate changes in cell cycle progression. These results demonstrate an essential role for a critical amount of STAT3 in the maintenance of an undifferentiated ES cell phenotype.

Research paper thumbnail of Acute phase response factor and additional members of the interferon-stimulated gene factor 3 family integrate diverse signals from cytokines, interferons, and growth factors

Journal of Biological Chemistry

Research paper thumbnail of Human antibodies to human RANKL, encoding nucleic acids and methods of treatment

Research paper thumbnail of Structural abnormalities associated with congenital megacolon in transgenic mice that overexpress theHoxa-4 gene

American Journal of Anatomy, 1993

Congenital megacolon develops in transgenic mice that overexpress the homeobox-containing gene, H... more Congenital megacolon develops in transgenic mice that overexpress the homeobox-containing gene, Hoxu-4. The current study was done to identify abnormalities of the terminal colon that might account for the phenotype. The terminal bowel of transgenic mice was compared with that of control and lethal spotted (ZslZs) mice, a strain in which megacolon also develops. The terminal colon of the transgenic mice 0 1993 WILEY-LISS, INC. that found in ZslZs mice. These data suggest that both smooth muscle and the innervation of the terminal bowel of neonatal Hoxu-4 transgenic mice are structurally abnormal. Although some of the abnormalities seen in Hoxu-4 transgenic mice are similar to those which arise in Zslls mice, the two conditions are not identical. In both animals, the data are consistent with the hypothesis that the defects arise as a result of a defective interaction between the precursors of enteric neurons and smooth muscle. o 1993 Wiley-Liss, Inc.

Research paper thumbnail of Análisis de un gen de pared celular y de una familia de secuencias moderadamente repetidas en los géneros "Zea" y "Sorghum" de Graminae: implicaciones evolutivas y funcionales

Research paper thumbnail of Cytoplasmic transcription factors: mediators of cytokine signaling

Agents and Actions Supplements, Feb 1, 1995

The distinct pattern of transcriptional responses of cells to different extracellular signals req... more The distinct pattern of transcriptional responses of cells to different extracellular signals requires a signal transduction pathway that provides rapid, accurate, and faithful transmission of information from the cell surface to the nucleus. One mechanism exploited by many cytokines, exemplified by interferons (IFN) but also used by many interleukins and growth factors, uses a family of cytoplasmic transcription factors that are activated by tyrosine phosphorylation. Once phosphorylated by receptor-associated tyrosine kinases, these proteins assemble into multimeric transcription factors, translocate to the nucleus, and bind specific DNA sequence elements in the promoters of target genes.

Research paper thumbnail of Stat3 is required for ALK-mediated lymphomagenesis and provides a possible therapeutic target

Nature Medicine, Jun 1, 2005

Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose t... more Anaplastic large cell lymphomas (ALCLs) are caused by chromosomal translocations that juxtapose the anaplastic lymphoma kinase (ALK) proto-oncogene to a dimerization partner, resulting in constitutive expression of ALK and ALK tyrosine kinase activity. One substrate of activated ALK in human ALCLs is the transcription factor Stat3, and its phosphorylation is accurately recapitulated in a new nucleophosmin (NPM)-ALK transgenic mouse model of lymphomagenesis. Here we show by gene targeting that Stat3 is required for the transformation of mouse embryonic fibroblasts in vitro, for the development of B-cell lymphoma in transgenic mice and for the growth and survival of both human and mouse NPM-ALK-transformed B and T cells. Ablation of Stat3 expression by antisense oligonucleotides significantly (P < 0.0001) impaired the growth of human and mouse NPM-ALK tumors in vivo. Pharmacological ablation of Stat3 represents a new candidate approach for the treatment of human lymphoma.

Research paper thumbnail of STAT1 mediates the increased apoptosis and reduced chondrocyte proliferation in mice overexpressing FGF2

Development (Cambridge, England), 2001

Unregulated FGF receptor signaling results in bone malformations that affect both endochondral an... more Unregulated FGF receptor signaling results in bone malformations that affect both endochondral and intramembranous ossification, and is the basis for several genetic forms of human dwarfism. FGF signaling inhibits chondrocyte proliferation and we have previously shown that the transcription factor STAT1 mediates the growth inhibitory effect of FGF in vitro. We provide genetic evidence that STAT1 is a modulator of the negative regulation of bone growth by FGF in vivo. We crossed Stat1(-/-) mice with a transgenic mouse line overexpressing human FGF2 (TgFGF). TgFGF mice exhibit phenotypes characterized by chondrodysplasia and macrocephaly, which affect endochondral and intramembranous ossification. We found that the chondrodysplasic phenotype of these mice results both from reduced proliferation and increased apoptosis of growth plate chondrocytes. Loss of STAT1 function in TgFGF mice led to a significant correction of the chondrodysplasic phenotype, but did not affect the skull malfor...

Research paper thumbnail of Structure-Function Analysis of ISGF3 Complex-Formation

Research paper thumbnail of Mechanisms of resistance to pathogen infections mediated by interferons signaling through the jak-Stat pathway

Research paper thumbnail of Genome-wide generation of knock-out mice and in vivo expression profiling using VelocigeneTM, a new high-throughput method, identifies novel genes expressed in bone and cartilage

Research paper thumbnail of Ror2 (W749X), a mutation carried by brachydactyly B patients, causes brachydactyly in the mouse and altered early cartilage development

Research paper thumbnail of Bmp3-Null Aged Mice Display Increased Trabecular Bone Volume and Reduced Cross Sectional Area at the Mid-Femoral Diaphysis

Research paper thumbnail of Stat3 and Ras activation are required for the cellular transformation mediated by NPM-ALK

Research paper thumbnail of A conditional null allele for the BMP antagonist noggin using a novel method for generating conditional knock-out mice

Research paper thumbnail of Cytoplasmic Transcription Factors: Mediators of Cytokine Signaling

Inflammation: Mechanisms and Therapeutics, 1995

The distinct pattern of transcriptional responses of cells to different extracellular signals req... more The distinct pattern of transcriptional responses of cells to different extracellular signals requires a signal transduction pathway that provides rapid, accurate, and faithful transmission of information from the cell surface to the nucleus. One mechanism exploited by many cytokines, exemplified by interferons (IFN) but also used by many interleukins and growth factors, uses a family of cytoplasmic transcription factors that are activated by tyrosine phosphorylation. Once phosphorylated by receptor-associated tyrosine kinases, these proteins assemble into multimeric transcription factors, translocate to the nucleus, and bind specific DNA sequence elements in the promoters of target genes.

Research paper thumbnail of The sequence of a hydroxyproline-rich glycoprotein gene from Sorghum vulgare

Plant Molecular Biology, 1991

Research paper thumbnail of Chromosome localization and characterization of a family of long interspersed repetitive DNA elements from the genus Zea

Theoretical and Applied Genetics, 1995

This paper describes the characterization and chromosomal distribution of new long repetitive seq... more This paper describes the characterization and chromosomal distribution of new long repetitive sequences present in all species of the genus Zea. These sequences constitute a family of moderately repetitive elements ranging approximately from 1350 to 1700 copies per haploid genome in modern maize (Zea mays ssp. mays) and teosinte (Zea diploperennis), respectively. The elements are long, probably larger than 9 kb, and they show a highly conserved internal organization among Zea subspecies and species. The elements are present in all maize chromosomes in an interspersed pattern of distribution, are absent from centromeric and pericentric heterochromatin, and with some clustering in the distal regions of chromosome arms.

Research paper thumbnail of Expression of a Maize Cell Wall Hydroxyproline-Rich Glycoprotein Gene in Early Leaf and Root Vascular Differentiation

THE PLANT CELL ONLINE, 1990

The spatial pattern of expression for a maize gene encoding a hydroxyproline-rich glycoprotein (H... more The spatial pattern of expression for a maize gene encoding a hydroxyproline-rich glycoprotein (HRGP) was determined by in situ hybridization. During normal development of roots and leaves, the expression of the gene was transient and particularly high in regions initiating vascular elements and associated sclerenchyma. Its expression was also associated with the differentiation of vascular elements in a variety of other tissues. The gene encoded an HRGP that had been extracted from the cell walls of maize suspension culture cells and several other embryonic and post-embryonic tissues. The gene was present in one or two copies in different varieties of maize and in the related monocots teosinte and sorghum. A single gene was cloned from maize using a previously characterized HRGP cDNA clone [Stiefel et al. (1988). Plant MOI. Biol. 11, 483-4931. In addition to the coding sequences for the HRGP and an N-terminal signal sequence, the gene contained a single intron in the nontranslated 3' end.

Research paper thumbnail of Three distinct loci on human chromosome 21 contribute to interferon-α/β responsiveness

Somatic Cell and Molecular Genetics, 1995

The species specificity of interferons (IFNs) depends on restricted recognition of these ligands ... more The species specificity of interferons (IFNs) depends on restricted recognition of these ligands by multisubunit cell surface receptors. Expression of the human receptor subunit IFNAR in mouse cells conferred sensitivity only to one subtype of human IFN, IFN-od3. Other genes on human chromosome 21 were required for responses to other subtypes of type I IFN. In contrast, IFNAR expression in hamster cells did not confer sensitivity to any human IFN tested, including IFN-ed3. Using human-hamster somatic cell hybrids, we mapped the Ifnabr gene, encoding a ligand-binding subunit of the IFN-ot/[3 (type I) receptor, to human chromosome 21. Ifnabr colocalized with Ifnar to the distal region of q22.1. The presence of a chromosomal fragment encoding IFNABR and IFNAR was also not sufficient to confer sensitivity to human IFN. In contrast, hybrids carrying in addition the region 21q22.2 showed a full response to human IFN-od3, suggesting that a gene located in this region encodes a third factor required for type I IFN receptor activity.

Research paper thumbnail of Essential role of STAT3 for embryonic stem cell pluripotency

Proceedings of the National Academy of Sciences, 1999

Propagation of mouse embryonic stem (ES) cells in vitro requires exogenous leukemia inhibitory fa... more Propagation of mouse embryonic stem (ES) cells in vitro requires exogenous leukemia inhibitory factor (LIF) or related cytokines. Potential downstream effectors of the LIF signal in ES cells include kinases of the Src, Jak, and mitogen-activated protein families and the signal transducer and transcriptional activator STAT3. Activation of nuclear STAT3 and the ability of ES cells to grow as undifferentiated clones were monitored during LIF withdrawal. A correlation was found between levels of STAT3 activity and maintenance of an undifferentiated phenotype at clonal density. In contrast, variation in STAT3 activity did not affect cell proliferation. The requirement for STAT3 was analyzed by targeted mutagenesis in ES cell lines exhibiting different degrees of LIF dependency. An insertional mutation was devised that abrogated Stat3 gene expression but could be reversed by Cre recombination-mediated excision. ES cells heterozygous for the Stat3 mutation could be isolated only from E14 cells, the line least dependent on LIF for self-renewal. Targeted clones isolated from other ES cell lines were invariably trisomic for chromosome 11, which carries the Stat3 locus, and retained normal levels of activated STAT3. Cre-regulated reduction of Stat3 gene copy number in targeted, euploid E14 clones resulted in dose-dependent losses of STAT3 activity and the efficiency of self-renewal without commensurate changes in cell cycle progression. These results demonstrate an essential role for a critical amount of STAT3 in the maintenance of an undifferentiated ES cell phenotype.