Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steel factor (SLF) and erythropoietin (Epo) play critical roles in erythropoiesis. To evaluate interactive effects of Epo and SLF receptors (R) in erythropoiesis, CD34+ and CD34 cord blood cells were transduced with human EpoR and c-kit cDNAs by retroviral mediated gene transfer. Erythroid (BFU-E) colonies derived from CD34+ or CD34 cells transduced with either the EpoR or c-kit gene were significantly increased in the presence of interleukin (IL)-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), Epo, and different concentrations of SLF compared with that from mock transduced cells. This number was further enhanced by co-transduction of both genes. Enhancement was more apparent in the absence of SLF. Cell numbers in individual erythroid colonies were also significantly increased in cells transduced with both genes compared with cells transduced with a single gene. Short-term liquid culture showed that ex vivo expansion for five days and numbers of CD34+CD71+ cells in expanded cells from single CD34 cells co-transduced with both EpoR and c-kit genes were increased compared with those of EpoR or c-kit-transduced cells. These results demonstrate that co-transduction of both c-kit and EpoR enhances the proliferative capacity of erythroid progenitors under cytokine stimulation above that of single-gene transduced cells.
Cytokines Cell Mol Ther 2000 Mar
PMID:Enhancing effects of co-transduction of both human erythropoietin receptor and c-kit cDNAs into hematopoietic stem/progenitor cells from cord blood on proliferation and differentiation of erythroid progenitors. 1097 33

Migrating cells are polarized with a protrusive lamella at the cell front followed by the main cell body and a retractable tail at the rear of the cell. The lamella terminates in ruffling lamellipodia that face the direction of migration. Although the role of actin in the formation of lamellipodia is well established, it remains unclear to what degree microtubules contribute to this process. Herein, we have studied the contribution of microtubules to cell motility by time-lapse video microscopy on green flourescence protein-actin- and tubulin-green fluorescence protein-transfected melanoma cells. Treatment of cells with either the microtubule-disrupting agent nocodazole or with the stabilizing agent taxol showed decreased ruffling and lamellipodium formation. However, this was not due to an intrinsic inability to form ruffles and lamellipodia because both were restored by stimulation of cells with phorbol 12-myristate 13-acetate in a Rac-dependent manner, and by stem cell factor in melanoblasts expressing the receptor tyrosine kinase c-kit. Although ruffling and lamellipodia were formed without microtubules, the microtubular network was needed for advancement of the cell body and the subsequent retraction of the tail. In conclusion, we demonstrate that the formation of lamellipodia can occur via actin polymerization independently of microtubules, but that microtubules are required for cell migration, tail retraction, and modulation of cell adhesion.
Mol Biol Cell 2000 Sep
PMID:Actin-dependent lamellipodia formation and microtubule-dependent tail retraction control-directed cell migration. 1098 96

The SH2 domain-containing tyrosine phosphatase PTPN6 (SHP-1, PTP1C, HCP) is a 68 kDa cytoplasmic protein primarily expressed in hematopoietic cell development, proliferation and receptor-mediated mitogenic signaling pathways. By means of direct dephosphorylation, it down-regulates a broad spectrum of growth-promoting receptors, including the Kit tyrosine kinase, activated to elicit a prominent cascade of intracellular events by stem cell factor binding. The pivotal contribution of PTPN6 in modulating myeloid cell signaling has been revealed by the finding that shp-1 mutation is responsible for the overexpansion and inappropriate activation of myelomonocytic populations in motheaten (me/me) and motheaten viable (me(v)/me(v)) mice. Association of PTPN6 with c-Kit and negative modulation of the myeloid leukocyte signal transduction pathways prompted us to examine the expression of the protein tyrosine phosphatase PTPN6 gene in CD34(+)/CD117(+) blasts from acute myeloid leukemia patients. We identified and cloned cDNAs representing novel PTPN6 mRNA species, derived from aberrant splicing within the N-SH2 domain leading to retention of intron 3. Sequence analysis of cDNA clones revealed multiple A-->G editing conversions. The editing of PTPN6 mRNA mainly occurred as an A-->G conversion of A(7866), which represents the putative branch site in IVS3 of PTPN6 mRNA. Evidence that editing of A(7866) abrogates splicing has been obtained in vitro by using an edited clone and its backward clone generated by site-directed mutagenesis. The level of the aberrant intron-retaining splice variant, evaluated by semi-quantitative RT-PCR, was lower in CD117(+)-AML bone marrow mononuclear cells at remission than at diagnosis, suggesting the involvement of post-transcriptional PTPN6 processing in leukemogenesis.
Hum Mol Genet 2000 Sep 22
PMID:RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. 1100 33

Accumulation of genetic damage in long-lived cell populations with proliferative capacity is implicated in tumorigenesis. Hematopoietic stem cells (hsc) maintain lifetime hematopoiesis, and recent studies demonstrate that hsc in leukemic patients are cytogenetically aberrant. We postulated that exposure to agents associated with increased leukemia risk would induce genomic changes in cells in the hsc compartment. Aneusomy involving chromosomes 2 and 11 in sorted hsc (Lin(-)c-kit(+)Sca-1(+)) and maturing lymphoid and myeloid cells from mice that received topical doses of benzene (bz) or trichloroethylene (TCE) was quantified using fluorescence in situ hybridization. Six days after bz or TCE exposure, aneuploid cells in the hsc compartment increase four- to eightfold in a dose- and schedule-independent manner. Aneuploid lymphoid and myeloid cells from bz- and TCE-treated mice approximate controls, except after repeated benzene exposures. Aneuploid cells are more frequent in the hsc compartment than in mature hematopoietic subpopulations. Hematotoxicity was also quantified in bz- and TCE-exposed hematopoietic subpopulations using two colony-forming assays: CFU-GM (colony-forming units/granulocyte-macrophage progenitors) and CAFC (cobblestone area-forming cells). Data indicate that bz is transiently cytotoxic (< or =1 week) to hsc subpopulations, and induces more persistent toxicity (>2 weeks) in maturing, committed progenitor subpopulations. TCE is not hematotoxic at the doses applied. In conclusion, we provide direct evidence for induction of aneuploidy in cells in the hsc compartment by topical exposure to bz and TCE. Disruption of genomic integrity and/or toxicity in hsc subpopulations may be one step in leukemic progression.
Environ Mol Mutagen 2001
PMID:Dermal benzene and trichloroethylene induce aneuploidy in immature hematopoietic subpopulations in vivo. 1131 36

Various growth factor receptors contain intrinsic tyrosine kinase activity, indicating that protein tyrosine kinases (PTK) play an important role in signal transduction pathways for cell proliferation and differentiation. To identify oocyte-derived factors which control follicle cells as well as oocyte-controlling factors produced by follicle cells, we examined the expression of genes which contain the PTK domain in the porcine ovary, using a polymerase chain reaction-based amplification technique with degenerate oligonucleotide primers that are specific to the PTK domain. Clones for the porcine homologues of platelet-derived growth factor receptor alpha (PDGFRalpha) and of insulin-like growth factor-I receptor (IGF-IR) were found during follicle growth both in oocytes and follicle cells. Clones for the porcine homologues of focal adhesion kinase (FAK), of c-kit and of fms-like tyrosine kinase (FLT)-3 were found only in oocytes. Moreover, after 24 h of in-vitro maturation of the cumulus-oocyte complexes, clones for the porcine homologues of FLT-1, of FLT-4, of Tie2 and of RYK in oocytes were observed. Immunohistochemical studies revealed the existence of PDGFRalpha, platelet-derived growth factor A (PDGFA), FAK and FLT3 in oocytes at various stages of folliculogenesis. These results suggest that fluctuations in the expression of these PTK genes may be involved in follicle growth and maturation.
Mol Hum Reprod 2001 Aug
PMID:Protein tyrosine kinase expression in the porcine ovary. 1147 Aug 59

Inefficient gene transfer has limited the success of gene therapy in the hematopoietic system. Here we develop a novel chimeric adenovirus (Ad) vector containing Ad serotype 11 fiber-modified capsids and E1/E3 deleted viral genomes (Ad5/11) or genomes devoid of all viral genes (DeltaAd5/11). The capsid-modified vectors transduced human hematopoietic cells more efficiently than the unmodified Ad5-based vector. The absence of viral genes from the DeltaAd5/11 vector allowed for transduction without the associated toxicity seen with the first-generation E1/E3 deleted vector. Chimeric vectors were used for transient expression of the ecotropic retrovirus receptor (ecoR) in Mo7e cells (a CD34-positive, c-Kit-positive, growth-factor-dependent human cell line) as a model for human hematopoietic progenitor cells. Expression of ecoR conferred susceptibility to subsequent retroviral transduction. The DeltaAd5/11 vector used to express ecoR allowed for expansion of retrovirally transduced cells, whereas transduction with the first-generation Ad5/11 vector resulted in cytotoxicity and, over time, loss of cells expressing the retrovirus-vector-derived transgene.
Mol Ther 2001 Jul
PMID:A capsid-modified adenovirus vector devoid of all viral genes: assessment of transduction and toxicity in human hematopoietic cells. 1147 4

Through differential screening of mouse hematopoietic stem cell (HSC) and progenitor-subtracted cDNA libraries we have identified a progenitor cell-specific transcript that represents a novel gene, named Hepp (hematopoietic progenitor protein). The mouse Hepp gene encodes a protein of 237 amino acids with no detectable known functional domains or motifs. Lack of invertebrate orthologs and a high degree of evolutionary conservation of the peptide sequence in vertebrate species (zebrafish, mouse, human) suggest that the Hepp gene could have conserved although as yet unknown function in vertebrates. Mouse Hepp shows a restricted expression pattern in adult tissues and is transcribed at a very low level in heart, lung, spleen, and thymus and at a higher level in muscle. During embryonic hematopoiesis Hepp is not expressed in mouse fetal liver HSC (Sca-1(+)c-kit(+)AA4.1(+)Lin(-) cells), but is abundantly transcribed in the population of hematopoietic progenitors (AA4.1(-) cells). Similarly, during adult hematopoiesis Hepp is not transcribed in the highly enriched population of bone marrow HSC (Rh-123(low)Sca-1(+)c-kit(+)Lin(-) cells), but its expression is upregulated as a greater heterogeneous population of bone marrow HSC (Lin(-)Sca-1(+) cells) differentiates into progenitors (Lin(-)Sca-1(-) cells) and more mature lymphoid and myeloid cell types. A restricted pattern of expression in adult tissues and preferential expression in both fetal and adult hematopoietic progenitors and mature blood cells suggest that Hepp could be involved in molecular regulation of HSC and progenitor cell lineage commitment and differentiation.
Blood Cells Mol Dis
PMID:Cloning and characterization of Hepp, a novel gene expressed preferentially in hematopoietic progenitors and mature blood cells. 1148 82

The RR5 monoclonal antibody (mAb) was obtained after immunization of mice with hemopoietic cells from chicken embryos. The cDNA encoding the protein recognized by RR5 was cloned using COS-7 cells transfected with an embryonic bone marrow (BM) cDNA library. The epitope recognized by the RR5 mAb was located on the non-polymorphic MHC class II beta-chain molecule. In the embryonic BM, RR5 labeled 50% of the c-kit expressing cells. Previous experiments have shown that the T-cell progenitors are present in the MHC class II(+)/c-kit(+) BM population along with myeloid progenitors and that T-cell and myeloid progenitors also express the integrin alphaIIbbeta3. In this study, using intrathymic cell transfer experiments in chicks, we have tested the T-cell differentiation potential of MHC class II/alphaIIbbeta3 double positive cells. It proved to be similar to that of the c-kit/MHC class II positive cells. However, injection of triple positive cells resulted in a selection of cells with an increased T-cell potential. Most of the MHC class II positive cells which do not express c-kit are prone to apoptosis, indicating that these progenitors might need a survival signal via c-kit. Interestingly, the MHC class II positive progenitors lose this expression after intrathymic transfer. Taken together our data suggest that the presence of the MHC class II beta-chain molecule on the surface of BM progenitor cells could be implicated in differentiation toward myeloid and lymphoid lineages.
Mol Immunol 2001 Jan
PMID:MHC class II beta-chain and alphaIIbbeta3 integrin are expressed on T-cell progenitors in embryonic bone marrow. 1148 9

The proto-oncogene receptor, c-kit, and its ligand have been demonstrated to be essential to the processes of germ cell migration, proliferation and survival in the rodent. The aim of the present study was to investigate the expression of c-kit mRNA and protein in human fetal ovary and testis across the gestational period 13-21 weeks. In the ovary, this crucial period of development spans the transition from oogonial replication by mitosis to primordial follicle formation. In the testis, germ cells (gonocytes) are mitotically active. Expression of c-kit mRNA was demonstrated by reverse transcription-polymerase chain reaction (RT-PCR) in both ovary and testis at all gestational ages examined. Testicular germ cell specific expression of c-kit mRNA was confirmed by RT-PCR using specific cell types recovered by laser capture microscopy. The expression of c-kit protein by both male and female germ cells was demonstrated by immunohistochemistry at all gestational ages examined, and was confirmed by immunoblotting. In both, c-kit was localized to the cell membrane except in oocytes within primordial follicles where it was localized to the cytoplasm. These data demonstrate that the expression of c-kit mRNA and protein is germ cell specific in human fetal gonads and are consistent with an important role for the c-kit/kit ligand signalling system in germ cell proliferation and survival in the developing human gonad.
Mol Hum Reprod 2001 Sep
PMID:Germ cell specific expression of c-kit in the human fetal gonad. 1151 91

Recent studies demonstrate that the normal progression of the germ cell lineage during gonadogenesis involves a delicate balance of primordial germ cell survival and death factors generated by surrounding somatic cells. This balance operates in a different fashion in females and males. The fine tuning primordial germ cell specification in the wall of the yolk sac, migration through the hindgut and dorsal mesentery, and colonization in the urogenital ridges involves the temporal and spatial activation of the following signaling pathways: Primordial germ cell specification involves bone morphogenetic proteins 2, 4 and 8b, and their migration is facilitated by the c-kit receptor-ligand duet. When colonization occurs: (1) neuregulin-beta ligand is expressed and binds to an ErbB2-ErbB3 receptor tyrosine kinase heterodimer on primordial germ cells; (2) Vasa, an ortholog of the Drosophila gene vasa, member of an ATP-dependent RNA helicase of the DEAD (Asp-Glu-Ala-Asp)-box family protein is also expressed by primordial germ cells; (3) Bcl-x (cell survival factor) and Bax (cell death factor) join forces to modulate the first burst of primordial germ cell apoptosis; (4) Cadherins, integrins, and disintegrins bring together primordial germ cells and somatic cells to organize testis and ovary. Information on other inducers of primordial cell survival, such as TER (teratoma) factor, is beginning to emerge.
Mol Reprod Dev 2001 Nov
PMID:Primordial germ cell-somatic cell partnership: a balancing cell signaling act. 1159 37


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