Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human monoblastoid leukemia U937 cells differentiate to monocyte/macrophage upon treatment with phorbol ester, 12-o-tetradecanoylphorbol-13-acetate (TPA). Previous studies, including our own, have demonstrated that drug-induced differentiation of leukemia cells is associated with genetic and enzymatic activations of protein tyrosine phosphatases (PTPases). In this study, to further investigate a relationship between PTPase activation and leukemic differentiation, we established TPA-resistant U937 variant UT16 cells. Unlike known TPA-resistant cells whose resistance is mainly due to lack or down modulation of protein kinase C (PKC), UT16 cells showed TPA-induced activation of PKC, Raf-1, and ERK/MAP kinases similar to the parental U937 cells. Interestingly, however, UT16 cells exhibited altered binding activity of AP-1 complexes, decreased ability to induce c-jun and c-fos gene expressions, and failure to differentiate to a monocytic lineage. Based on these observations, UT16 cells could be considered a novel type of TPA-resistant cell. Among UT16 cells, most of TPA-inducible PTPase genes, PTP-1C, PTP-MEG2, P19-PTP, HPTP epsilon, and PTP-U1, did not respond to TPA. Consistently, TPA increased PTPase enzymatic activity in U937 but not in UT16 cells. Taken together, activation of PTPases is well correlated with TPA-induced differentiation of U937 cells. These findings indicate that gene expression and enzymatic activity of some PTPase isozymes described here are regulated by a TPA-mediated signaling event and are likely to be used as biomarkers for the monocytic differentiation of myeloid leukemia cells.
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PMID:Phorbol ester-resistant monoblastoid leukemia cells with a functional mitogen-activated protein kinase cascade but without responsive protein tyrosine phosphatases. 747 24

Previously, we cloned two gene fragments encoding novel protein tyrosine phosphatases, termed PTP-U1 and PTP-U2. Here, we report the full-length sequence, expression, and chromosomal localization of the PTP-U2 gene. The cDNA for PTP-U2, which was obtained from a human normal kidney library, predicts a protein of 1216 amino acids, -140 kDa, that contains a single transmembrane domain and a single intracellular catalytic domain. The extracellular domain of PTP-U2 contains 14 putative N-glycosylation sites and eight repeats of fibronectin type III-like motif. These data suggest that PTP-U2 is structurally similar to HPTP beta and DPTP10D, which have been reported previously. Northern blot analysis revealed that there were two different transcripts for PTP-U2. In kidney and brain, gene expression of PTP-U2 was detected as a 5.4 kb mRNA and in lung and placenta as 3.5 kb. The 3.5 kb transcript was also detected in human leukemia cell lines (eg., U937). Interestingly, its gene expression was enhanced by various differentiation-inducing agents, such as phorbol ester, dihydroxy vitamin D3, retinoic acid, and dimethyl sulfoxide. The bacterially expressed PTP-U2 fusion protein exhibited intrinsic tyrosine phosphatase activity. The PTP-U2 gene was assigned to chromosome 12p13.2-p13.3.
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PMID:Cloning, expression and chromosomal localization of a novel gene for protein tyrosine phosphatase (PTP-U2) induced by various differentiation-inducing agents. 775 50

Some human leukemia cell lines, such as HL-60 and U937, differentiate to monocyte/macrophage by treatment with chemicals such as phorbol ester or 1,25-dihydroxy vitamin D3. In this report, we demonstrate that cellular protein tyrosine phosphatase (PTPase) activity (especially in cytosol) in monoblastoid leukemia U937 cells increased up to 2-fold during the course of monocytic differentiation. We have cloned 13 PTPase-related gene fragments from the differentiated U937 cells using the reverse transcription-polymerase chain reaction method. Two of these were found to be genes of novel isozymes, PTP-U1 and PTP-U2. We investigated the changes in expression of each isozyme during the differentiation of the cells and found that nine isozymes (both cytosolic and transmembranous) were expressed more in the differentiated cells than in the undifferentiated cells. Among them, PTP-U1 and PTP-U2 were greatly induced by phorbol ester. Interestingly, there were two cytosolic isozymes that were down-regulated during the course of differentiation. Our present data suggest that the functions of the PTPase isozyme during monocytic maturation are not always equivalent to each other, and tyrosine dephosphorylation may participate in several different pathways of signal transduction during the differentiation of leukemia cells.
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PMID:Differential expression of protein tyrosine phosphatase genes during phorbol ester-induced differentiation of human leukemia U937 cells. 811 17

The erythro-megakaryoblastic leukemia cell line K562 undergoes erythroid or myeloid differentiation in response to treatment with various inducing agents. We observed that expression of the SH2-containing protein tyrosine phosphatase SHP-1 was induced upon exposure of K562 cells to differentiating agents. Under the same conditions, expression of SHP-2, a close relative of SHP-1, and the more distantly related PTP-1 B remained unchanged. Induction of SHP-1 expression correlates with dephosphorylation of a specific and limited set of tyrosyl phosphoproteins, suggesting that dephosphorylation of these proteins may be important for the differentiation process. Importantly, expression of exogenous SHP-1 inhibits K562 proliferation and alters the adhesion properties of these cells, indicating a more differentiated phenotype. Moreover, SHP-1 is found in a complex with both p210 Bcr-Abl and p190 Bcr-Abl, suggesting that it may regulate Bcr-Abl or Bcr-Abl-associated phosphotyrosyl proteins. Our results indicate that induction of SHP-1 expression is important for K562 differentiation in response to various inducers and raise the possibility that functional inactivation of SHP-1 may play a role in progression to blast crisis in chronic myelogenous leukemia.
Leukemia 2001 Sep
PMID:Role of the tyrosine phosphatase SHP-1 in K562 cell differentiation. 1151 3

Protein tyrosine phosphorylation is a dynamic reversible process in which the level of phosphorylation, at any time, is the result of phosphatase and/or kinase activity. This balance is critical for control of growth and differentiation. The role of tyrosine phosphatases during nephrogenesis and in kidney disease requires delineation. Appropriate regulation of focal adhesion proteins such as focal adhesion kinase (FAK) and paxillin are important in cell adhesion, migration, and differentiation. We have previously shown that B cell lymphoma/leukemia-2 (bcl-2) -/- mice develop cystic kidneys and exhibit sustained phosphorylation of FAK and paxillin. We have examined the expression and activity of focal adhesion tyrosine phosphatases [Src homology-2 domain phosphatase (SHP-2), protein tyrosine phosphatase (PTP 1B), and PTP-proline, glutamate, serine, and threonine sequences (PEST)] during normal nephrogenesis and in cystic kidneys from bcl-2 -/- mice. Cystic kidneys from postnatal day 20 bcl-2 -/- mice demonstrate a reduced expression, sixfold decrease in activity, and altered distribution of SHP-2 and PTP 1B. PTP-PEST expression and distribution were similar in both bcl-2 +/+ and bcl-2 -/- mice. The altered regulation of PTP 1B and SHP-2 in kidneys from bcl-2 -/- mice correlates with sustained phosphorylation of FAK and paxillin. Thus renal cyst formation in the bcl-2 -/- mice may be the result of an inability of complete differentiation due to continued activation of growth processes, including activation of FAK and paxillin.
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PMID:Altered regulation of SHP-2 and PTP 1B tyrosine phosphatases in cystic kidneys from bcl-2 -/- mice. 1183 24

Stimulus-induced secretion of bioactive polypeptides is a fundamental aspect of the immune system. Secretory proteins are synthesized in the endoplasmic reticulum and are transported through the Golgi apparatus to the trans-Golgi network, where they are sorted into transport vesicles that bud off and fuse into condensing vacuoles, which subsequently undergo an editing and concentration process to become mature secretory vesicles. In this study, we report that the PTP-MEG2 protein tyrosine phosphatase is located on these vesicles in mast cells. Expression of PTP-MEG2 caused a striking enlargement of these vesicles in both rat basophilic leukemia mast cells and Jurkat T leukemia cells into giant vesicles with diameters of up to several micrometers. The fused vesicles did not acquire markers for other compartments and were adjacent to the trans-Golgi network, contained carboxypeptidase E, chromogranin C, and IL-2, and had an electron-dense core typical of secretory vesicles. Expression of PTP-MEG2 also caused a reduction in the secretion of IL-2 from stimulated Jurkat cells. The effects of PTP-MEG2 on secretory vesicles required the catalytic activity of PTP-MEG2 and was rapidly reversed by pervanadate. We propose that PTP-MEG2 represents a novel connection between tyrosine dephosphorylation and the regulation of secretory vesicles in hematopoietic cells.
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PMID:Enlargement of secretory vesicles by protein tyrosine phosphatase PTP-MEG2 in rat basophilic leukemia mast cells and Jurkat T cells. 1197 Oct 9

Recently, we reported that a cytosolic isoform of protein-tyrosine phosphatase epsilon (PTP epsilon C), when overexpressed, inhibits terminal differentiation and apoptosis of murine M1 myeloblastic leukemia cells induced by interleukin-6. To determine whether these observed effects in vitro correspond to a tumorigenicity of PTP epsilon C-expresser (M1- epsilon C) cells in vivo, parent M1 and M1- epsilon C cells were intravenously inoculated into scid or nude mice, and survival of mice receiving these cell lines was monitored. Unexpectedly, both scid and nude mice inoculated with M1- epsilon C cells showed significantly prolonged survival time than those receiving parent M1 cells. While parent M1 cells inoculated by intravenous injection formed metastatic tumors in the spleen, expression of PTP epsilon C suppressed tumor development in the spleen. The results suggest a suppressive role of PTP epsilon C in tumorigenesis.
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PMID:Reduced tumorigenicity of murine leukemia cells expressing protein-tyrosine phosphatase, PTPepsilon C. 1266 Aug 11

In tumour cells, elevated levels of mitochondria-bound isoforms of hexokinase (HK-I and HK-II) result in the evasion of apoptosis, thereby allowing the cells to continue proliferating. The molecular mechanisms by which bound HK promotes cell survival are not yet fully understood. Our studies relying on the purified mitochondrial outer membrane protein VDAC (voltage-dependent anion channel), isolated mitochondria or cells in culture suggested that the anti-apoptotic activity of HK-I occurs via modulation of the mitochondrial phase of apoptosis. In the present paper, a direct interaction of HK-I with bilayer-reconstituted purified VDAC, inducing channel closure, is demonstrated for the first time. Moreover, HK-I prevented the Ca(2+)-dependent opening of the mitochondrial PTP (permeability transition pore) and release of the pro-apoptotic protein cytochrome c. The effects of HK-I on VDAC activity and PTP opening were prevented by the HK reaction product glucose 6-phosphate, a metabolic intermediate in most biosynthetic pathways. Furthermore, glucose 6-phosphate re-opened both the VDAC and the PTP closed by HK-I. The HK-I-mediated effects on VDAC and PTP were not observed using either yeast HK or HK-I lacking the N-terminal hydrophobic peptide responsible for binding to mitochondria, or in the presence of an antibody specific for the N-terminus of HK-I. Finally, HK-I overexpression in leukaemia-derived U-937 or vascular smooth muscle cells protected against staurosporine-induced apoptosis, with a decrease of up to 70% in cell death. These results offer insight into the mechanisms by which bound HK promotes tumour cell survival, and suggests that its overexpression not only ensures supplies of energy and phosphometabolites, but also reflects an anti-apoptotic defence mechanism.
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PMID:In self-defence: hexokinase promotes voltage-dependent anion channel closure and prevents mitochondria-mediated apoptotic cell death. 1456 Dec 15

Deficiency in either the interferon consensus sequence binding protein (ICSBP) or neurofibromin 1 (Nf1) increases the proliferative response of myeloid progenitor cell to hematopoietic cytokines. Consistent with this, we previously demonstrated that ICSBP activates transcription of the gene encoding Nf1 (the NF1 gene). In the studies presented here, we determine that ICSBP tyrosine phosphorylation is necessary for the activation of NF1 transcription. Since ICSBP is tyrosine phosphorylated in response to hematopoietic cytokines, these studies identify a novel pathway by which cytokine-induced posttranslational modification of ICSBP results in NF1 transcription. Nf1 subsequently inactivates cytokine-activated Ras, thereby creating a negative feedback mechanism for cytokine-induced proliferation. In these studies, we also determine that ICSBP is a substrate for SHP2 protein tyrosine phosphatase (SHP2-PTP). We find that wild-type SHP2-PTP dephosphorylates ICSBP only in undifferentiated myeloid cells. In contrast, a leukemia-associated, constitutively activated mutant form of SHP2-PTP dephosphorylates ICSBP in both myeloid progenitors and differentiating myeloid cells. Activated SHP2-PTP mutants thereby inhibit ICSBP-dependent NF1 transcription, impairing this negative feedback mechanism on cytokine-activated Ras. Therefore, these studies suggest that leukemia-associated ICSBP deficiency cooperates with leukemia-associated activating mutants of SHP2-PTP to contribute to the proliferative phenotype in myeloid malignancies.
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PMID:Leukemia-associated, constitutively active mutants of SHP2 protein tyrosine phosphatase inhibit NF1 transcriptional activation by the interferon consensus sequence binding protein. 1691 19

Mutations of the protein tyrosine phosphatase SHP-2 are implicated in human diseases, causing Noonan syndrome (NS) and related developmental disorders or contributing to leukemogenesis depending on the specific amino acid substitution involved. SHP-2 is composed by a catalytic (PTP) and two regulatory (N-SH2 and C-SH2) domains that bind to signaling partners and control the enzymatic activity by limiting the accessibility of the catalytic site. Wild type SHP-2 and four disease-associated mutants recurring in hematologic malignancies (Glu76Lys and Ala72Val) or causing NS (Glu76Asp and Ala72Ser), with affected residues located in the PTP-interacting region of the N-SH2 domain, were analyzed by molecular dynamics simulations and in vitro biochemical assays. Simulations demonstrate that mutations do not affect significantly the conformation of the N-SH2 domain. Rather they destabilize the interaction of this domain with the catalytic site, with more evident effects in the two leukemia associated mutants. Consistent with this structural evidence, mutants exhibit an increased level of basal phosphatase activity in the order Glu76Lys > Ala72Val > Glu76Asp > Ala72Ser > WT. The experimental data also show that the mutants with higher basal activity are more responsive to an activating phosphopeptide. A thermodynamic analysis demonstrates that an increase in the overall phosphopeptide affinity of mutants can be explained by a shift in the equilibrium between the inactive and active SHP-2 structure. These data support the view that an increase in the affinity of SHP-2 for its binding partners, caused by destabilization of the closed, inactive conformation, rather than protein basal activation per se, would represent the molecular mechanism, leading to pathogenesis in these mutants.
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PMID:Structural and functional effects of disease-causing amino acid substitutions affecting residues Ala72 and Glu76 of the protein tyrosine phosphatase SHP-2. 1717 98


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