Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10721 (c-kit)
 6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Erythropoiesis is considered to be the result of a series of molecular events which alter gene expression. Recently, advances have been made in the understanding of several aspects of erythroid gene expression. A variety of transcription factors are now known to control expression of specific genes in the nucleus. Some of these are influenced by action of cytokines at the cell surface, an example of which is the interaction of c-kit with its ligand, the stem cell factor. Abnormalities in the regulation of transcription factor genes are implicated in leukemogenesis. Furthermore, an additional level of complexity in gene expression is provided post-transcriptionally, by which alternative splicing of RNA transcripts result in erythroid-specific proteins. In this way, changes in gene expression in erythroid progenitor cells directly contribute to the formation of the mature erythrocyte.
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PMID:Gene expression during erythropoiesis. 164 90

A panel of 164 continuous human leukemia-lymphoma cell lines was analyzed for expression of c-kit using Northern blotting and reverse transcriptase-polymerase chain reaction (RT-PCR). The c-kit transcripts were detectable in cell lines assigned to the myeloid (in 7 of 29 by Northern blotting and in 4 of 8 by RT-PCR), monocytic (in 1 of 24 by Northern blotting and in 3 of 6 by RT-PCR), erythroid (in 6 of 8 by Northern blotting and in 5 of 5 by RT-PCR), and megakaryoblastic (in 10 of 10 by Northern blotting) lineages, c-kit expression was not seen by Northern blotting or RT-PCR analysis in any of the 93 lymphoid leukemia, myeloma, or lymphoma cell lines. Treatment of four megakaryoblastic cell lines with protein kinase C activators (phorbol ester 12-O-tetradecanoylphorbol 13-acetate and Bryostatin 1) led to terminal differentiation as assessed by morphologic alterations, changes in the surface marker profile, and growth arrest. These effects were associated with enhanced c-kit mRNA expression. Exposure to all-trans retinoic acid down-regulated c-kit mRNA levels, while simultaneously causing morphologic alterations in all four cell lines. Stimulation with growth factors (interleukin-3, granulocyte macrophage-colony stimulating factor, and insulin-like growth factors I and II), used to assess any role of c-kit in proliferative processes, did not lead to significant upregulation or downregulation of c-kit expression. The finding of constitutive and high expression of c-kit mRNA in all megakaryoblastic leukemia cell lines and its modulation by various reagents might further contribute to the understanding of megakaryopoietic proliferation, differentiation, and leukemogenesis.
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PMID:c-kit expression in human megakaryoblastic leukemia cell lines. 751 41

Understanding how self renewal, commitment and differentiation are regulated in normal, multipotent hematopoietic progenitors is important for our understanding of underlying mechanisms involved in leukemogenesis. In addition, knowledge of progenitor cell biology is critical if these cells are to be used for gene therapy. In this communication, we demonstrate that the oncogenic transcription factor v-Ski, together with the ligand activated receptor tyrosine kinase c-Kit, induces the continuous in vitro self renewal of primary avian multipotent progenitors. These cells have an in vitro life span of > 100 generations. In addition they spontaneously differentiate into cells of the erythroid, monocytic and granulocytic lineages. If clonal strains of these multipotent progenitors are exposed to specific mixtures of growth factors and hormones, they develop into committed cells of either the erythroid or myeloid lineages. These committed cells underwent efficient terminal differentiation when they were treated with the relevant lineage-specific growth/differentiation factors, but underwent apoptosis when exposed to the incorrect factors for the respective lineage. While the committed cells coexpress marker proteins from different lineages, expression of the 'wrong' lineage marker is repressed during terminal differentiation. Our results indicate that a combination of v-Ski and activated c-Kit induces long-term self renewal in primary multipotent progenitors, which can be induced to commit and differentiate along specific lineages under different, defined conditions. Our data also suggest that growth factors and steroid hormones control terminal differentiation by a combined induction of commitment, growth and apoptosis, a process likely to be affected in stem cell leukemias.
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PMID:In vitro growth of factor-dependent multipotential hematopoietic cells is induced by the nuclear oncoprotein v-Ski. 762 32

Accumulating evidence suggests that c-kit and its ligand, stem cell factor (SCF), play an important role in the regulation of at least three lineages of stem cell growth and possibly in leukemogenesis, while only limited data are available that suggest possible involvement of c-kit/SCF in the development of human solid tumors such as lung cancer. We have recently reported that c-kit is aberrantly expressed almost exclusively in small-cell lung cancer (SCLC) among various types of solid tumors. The present study revealed that c-kit protein ectopically expressed in SCLC is indistinguishable from that in leukemia cell lines with megakaryocytic characteristics with respect to amount, molecular size, and autophosphorylation status in response to recombinant human SCF. Furthermore, significant chemotactic response as well as moderate in vitro cell growth was induced in SCLC cell lines by the addition of recombinant human SCF, suggesting that c-kit/SCF may play an important biological role in the development of SCLC. Our extensive search for activating mutations naturally occurring in the c-kit gene revealed an amino acid substitution in the transmembrane domain of an SCLC cell line, although the functional consequences of this variant allele are yet to be determined.
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PMID:Recombinant human stem cell factor mediates chemotaxis of small-cell lung cancer cell lines aberrantly expressing the c-kit protooncogene. 768 Sep 56

A novel human leukemia cell line (Kasumi-3) was established from the blast cells of a 57-year-old man suffering from myeloperoxidase-negative acute leukemia. The cell line had five distinctive features, as follows. 1) Flow cytometric analyses showed cell surface expression of CD7, CD4, CD13, CD33, CD34, HLA-DR and c-Kit. This phenotype is compatible with that of acute myelocytic leukemia cells with the M0 subtype in the French-American-British classification. 2) Kasumi-3 cells carried chromosomal abnormalities of t(3;7)(q27:q22), del(5)(q15), del(9)(q32), and add(12)(p11). The breakpoint of 3q27 was located near the EVI1 gene, and a high level of expression of the EVI1 gene was observed. 4) Kasumi-3 cells treated with TPA showed maturation to monocytic lineage. 5) Treatment with either interleukin (IL)-2, IL-3, IL-4, granulocyte-macrophage colony-stimulating or stem cell factor induced the proliferation of Kasumi-3 cells. Thus, the Kasumi-3 cell line shows the characteristic features of undifferentiated leukemia. It should, therefore, be useful both for studying the biological characteristics of acute myelogenous leukemia M0 subtype and for investigating the role of the EVI1 gene in leukemogenesis.
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PMID:Establishment of an undifferentiated leukemia cell line (Kasumi-3) with t(3;7)(q27;q22) and activation of the EVI1 gene. 861 29

To clarify whether the expression of the WT1 gene in leukemic cells is aberrant or merely reflects that in normal counterparts, the expression levels of the WT1 gene were quantitated for normal hematopoietic progenitor cells. Bone marrow (BM) and umbilical cord blood (CB) cells were fluorescence-activated cell sorting (FACS)-sorted into CD34+ and CD34- cell populations, and the CD34+ cells into nine subsets (CD34+ CD33-, CD34+ CD33+, CD34+ CD38-, CD34+ CD38+, CD34+ HLA-DR-, CD34+ HLA-DR+, CD34+ c-kit(high), CD34+ c-kit(low), and CD34+ c-kit-) according to the expression levels of CD34, CD33, CD38, HLA-DR, and c-kit. Moreover, acute myeloid leukemic cells were also FACS-sorted into four populations (CD34+ CD33-, CD34+ CD33+, CD34- CD33+, and CD34- CD33-). FACS-sorted normal hematopoietic progenitor and leukemic cells and FACS-unsorted leukemic cells were examined for the WT1 expression by quantitative reverse transcriptase-polymerase chain reaction. The WT1 expression in the CD34+ and CD34- cell populations and in the nine CD34+ subsets of BM and CB was at either very low (1.0 to 2.4 x 10(-2)) or undetectable (< 10(-2)) levels (the WT1 expression level of K562 cells was defined as 1.0), whereas the average levels of WT1 expression in FACS-sorted and -unsorted leukemic cells were 2.4 to 9.3 x 10(-1). Thus, the WT1 expression levels in normal hematopoietic progenitor cells were at least 10 times less than those in leukemic cells. Therefore, we could not find any normal counterparts of BM or CB that expressed the WT1 at levels comparable with those in leukemic cells. These results indicate an aberrant overexpression of the WT1 gene in leukemic cells and imply the involvement of this gene in human leukemogenesis.
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PMID:Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. 902 64

V-ErbA, a mutated thyroid hormone receptor (TR) alpha cooperates with tyrosine kinase oncoproteins to induce fatal erythroleukemia in chicks. In vitro, v-ErbA employs a similar cooperation to induce sustained proliferation and arrest differentiation of committed erythroid progenitors. V-ErbA has been proposed to function as a dominant-negative c-ErbA/TR alpha, since it lacks an AF-2 transactivation domain and cannot be activated by hormone but retains the capacity to bind corepressors. However, v-ErbA fails to heterodimerize with the coreceptor RXR, exhibits an altered DNA binding specificity and fails to suppress the action of coexpressed TR alpha/c-ErbA in erythroblasts. In this paper, we identify a novel mechanism by which v-ErbA contributes to leukemogenesis. Recently, the glucocorticoid receptor (GR) was identified as a key regulator of proliferation and differentiation in normal erythroid progenitors. For this, the GR required to cooperate with endogenous receptor tyrosine kinases (c-Kit) and with the estrogen receptor (ER). Here, we demonstrate that v-ErbA can substitute for the ligand-activated GR and ER, inducing proliferation and arresting differentiation in the presence of specific GR and ER antagonists. Like the GR, v-ErbA required to cooperate with c-Kit for both proliferation induction and differentiation arrest, being devoid of biological activity in the absence of an active c-Kit. In self-renewing erythroblasts, v-ErbA not only repressed known v-ErbA target genes but also maintained high expression of c-myb. These biological activities of v-ErbA depended on distinct mutations in the DNA-binding domain. Additionally, v-ErbA acted as a partial, weak repressor of c-ErbA/TR alpha function in normal erythroblasts. It could be converted into a truly dominant-negative receptor by restoring its ability to heterodimerize with RXR.
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PMID:Mechanism of transformation by v-ErbA: substitution for steroid hormone receptor function in self renewal induction. 926 11

We evaluated the effect of SCF on myeloid differentiation by correlating clonogenic potential (as CFU-GM), bone marrow (BM) plasma SCF levels and CD34/c-kit expression in 57 MDS samples. There was a significant correlation between low SCF levels and 'leukemic' in vitro growth, the number of clusters and the colony/cluster ratio. No correlation was found between BM plasma SCF levels, the pattern of growth and CD34+ c-kit+ expression. These data seem to exclude any direct effect of SCF on leukemogenesis, but suggest that low plasma SCF levels may be at least partially responsible for leukemic growth in MDS.
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PMID:Low plasma stem cell factor levels correlate with in vitro leukemic growth in myelodysplastic syndromes. 1007 Oct 80

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.
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PMID:RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia. 1100 33

Benzene (bz) is a common environmental contaminant associated with increased risk of myeloid leukemia. Chronic bz exposure in vivo increases the frequency of aneuploid circulating lymphocytes in humans. However, there is no information about persistence of bz-associated aneuploidy in immature/primitive cells, at risk of leukemic transformation, after bz exposure in vivo. We explored the relationship between the induction and persistence of aneuploidy in primitive hemopoietic cells from mice that received oral doses of bz in vivo. Short- and long-term persistence of aneuploidy were evaluated in immature/primitive sub-populations (Lin(-)c-kit(+)Sca-1(+)), as well as lymphoid and myeloid cells, 6 days and 2-8 months after exposure. Mice receiving bz in a corn oil carrier, or corn oil alone, both have increased aneuploidy frequencies (1-5%, compared to <1% in untreated controls) in all sub-populations, 6 days after exposure. However, unlike bz-induced aneuploidy, corn oil-induced aneusomies are transient, with frequencies returning to background levels in lymphoid and myeloid cells, 9 weeks after exposure. The frequency (5-9%) of aneuploid lymphocytes and myeloid cells is higher at 9 weeks than at 6 days, suggesting that bz disrupts chromosomal segregation in differentiated cells and/or progenitors. About 8 months after bz exposure, the Lin(-)c-kit(+)Sca-1(+) sub-population contains up to 14% aneuploid cells with numerical chromosomal aberrations affecting chromosomes 2 or 11. These data demonstrate that bz induces DNA copy number changes in immature/primitive cells, and that these changes persist for long periods. Although, initial exposures are not leukemogenic, subsequent exposures of cells to genotoxins or oxidative radicals that induce additional genetic hits may increase the risk of transformation. The contribution of bz-induced aneuploidy in immature/primitive cells to leukemogenesis remains to be determined.
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PMID:Persistence of aneuploid immature/primitive hemopoietic sub-populations in mice 8 months after benzene exposure in vivo. 1128 6


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