Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Strong and heritable increase of immunogenicity of L1210 Ha leukemia has been obtained in vitro following multiple treatments with 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC), metabolically activated by mouse liver preparations (MLP) containing liver microsomes. The DTIC-treated leukemia (L1210D line) or the control line treated with MLP alone (L1210N line) showed comparable growth kinetics in vitro. However, progressive increase of immunogenicity occurred in leukemic cells in the course of in vitro treatments with DTIC plus MIP, but not with MLP alone, as evidenced by comparative studies on transplantation immunity elicited in BALB/c x DBA/2 F1 mice by graded inocula of L1210D or L1210N leukemia cells. In vitro experiments confirmed that metabolic transformation of DTIC is required for increasing tumor immunogenicity. In fact, L1210Ha cells became highly immunogenic when treated with DTIC in intact mice but not in animals metabolically depressed by CCl4. Immunochemotherapy experiments based on the antigenic cross-reactivity between the L1210D line and the original L1210Ha leukemia showed that i.p. administration of L1210D cells followed by 1,3-bis(2-chloroethyl)-1-nitrosourea treatment afforded marked protection in mice inoculated intracerebrally with the parental lymphoma. The present findings could provide an adequate in vitro technique for developing further studies on DTIC-mediated immunogenic changes of tumors, including human cancer cells growing in tissue culture.
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PMID:In vitro generation of a highly immunogenic subline of L1210 leukemia following exposure to 5-(3,3'-dimethyl-1-triazeno)imidazole-4-carboxamide. 701 15

The CD44 cell surface glycoprotein is expressed on a broad range of different tissues as multiple isoforms containing from one to ten alternatively spliced exons v1-v10 inserted within the extracellular domain. Differential glycosylation generates still further variability, yielding both N- and O-glycan-modified forms of CD44 in addition to proteoglycan-like variants containing chondroitin sulphate and heparan sulphate. These high molecular mass proteoglycan-like variants, previously identified in lymphocytes, melanomas, and keratinocytes have been implicated in cell-matrix adhesion, cell motility, and invasiveness. More recently, monocyte CD44 molecules presumed to carry glycosaminoglycan chains were shown to bind the chemokine MIP-1 beta (Tanaka, Y.,D. H. Adams, S. Hubscher, H. Hirano, U. Siebenlist, and S. Shaw. 1993. Nature (Lond). 361:79-82.) raising the intriguing possibility that proteoglycan-like CD44 variants might play a role in regulating inflammatory responses. Here we have investigated the molecular identity of these proteoglycan-like CD44 variants by generating a panel of recombinant CD44 isoforms using a novel cassette cloning strategy. We show that both chondroitin and heparan sulphate modifications are associated specifically with isoforms (CD44v3-10 and CD44v3,8-10) containing the v3 alternative exon which encodes a consensus motif SGXG for GAG addition. Other isoforms (CD44v10, CD44v8-10, CD44v7-10, and CD44v6-10) are shown to lack these GAG chains but to carry extensive O-glycan modifications, most likely within the mucin-like alternative exon inserts. We also demonstrate that the majority of endogenous GAG-modified CD44 isoforms present in epithelial cells constitute v3 isoforms thus establishing that in these cells the majority of proteoglycan-like CD44 variants are generated by alternative splicing. Finally we present evidence using transfected B lymphoma cells that the GAG-modified CD44 isoforms CD44v3-10 and CD44v3,8-10, unlike CD44H, bind only weakly to hyaluronan. Together with the demonstration in the accompanying paper (Bennett, K., D. G. Jackson, J.C. Simon, E. Tanczos, R. Peach, B. Modrell, I. Stamenkovic, G. Plowman, and A. Aruffo. 1995. J. Cell Biol. 128:687-698.), that CD44 molecules containing the v3 exon bind growth factors, these results highlight a new and potentially important role for CD44 alternative splicing in the control of cell-surface proteoglycan expression.
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PMID:Proteoglycan forms of the lymphocyte homing receptor CD44 are alternatively spliced variants containing the v3 exon. 753 75

Chronic myeloid leukemia (CML) has long served as a prototype malignancy for basic as well as clinical studies aimed at developing curative cancer treatment protocols. Well established features of chronic phase CML are its origin in a pluripotent stem cell, a now well defined molecular genetic basis involving the creation of a BCR-ABL fusion gene and evidence of resultant abnormalities in the mechanisms that normally control primitive hemopoietic cell proliferation. We have recently shown how the long-term marrow culture system can be adapted to quantitate and characterize a very primitive cell type in normal blood and marrow samples, as well as their normal and leukemic counterparts in patients with CML. This system has also been used to dissect mechanisms of normal progenitor regulation and to identify specific anomalies affecting leukemic (CML) progenitors. Our studies show that cells detected by their ability to initiate long-term cultures (LTC) of leukemic cells (i.e., CML LTC-initiating cells or LTC-IC) are differently distributed between marrow and blood by comparison to LTC-IC in normal individuals and, although functionally similar in terms of the number and differentiation types of clonogenic cells they produce, CML LTC-IC exhibit defective self-maintenance. Phenotypically these primitive leukemic cells are heterogeneous; the majority display features of activated/proliferating cells but a significant proportion do not. We have also documented heterogeneity in primitive CML cell responses to two factors that specifically and reversibly arrest the cycling of primitive normal hemopoietic cells; i.e., TGF-beta and MIP-1 alpha, to which CML cells are normally responsive and abnormally unresponsive, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Leuk Lymphoma 1993
PMID:The biology of normal and neoplastic stem cells in CML. 825 4

Myeloproliferative disorders (MPD) are characterized by several common clinical and biological features, although at the molecular level, each disease entity exhibits distinct abnormalities. IFN-alpha exerts beneficial therapeutic effects in chronic myelogenous leukemia, polycythemia vera and essential thrombocythemia, resulting in control of hematopoietic hyperplasia and, in a minority of patients, in induction of cytogenetic remission. The mechanism of action of IFN-alpha in MPD is poorly defined. Recently published in vitro findings suggest that IFN-alpha interacts with the regulation of hematopoiesis by multiple ways. Its antiproliferative activity is well known for more than a decade, however, substantial growth inhibition is achieved only at relatively high concentrations. Defective adhesion of hematopoietic progenitor cells in CML to bone marrow stromal cells is corrected by IFN-alpha, which might expose CML progenitors to inhibitory cytokines produced by the bone marrow microenvironment. Recent work from our group demonstrated, that IFN-alpha potently interacts with the production of hematopoietic cytokines in bone marrow stromal cells. Expression of stimulatory cytokines, such as GM-CSF, G-CSF, IL-1 and IL-11 is inhibited by IFN-ct, whereas the production of negative regulators, such as IL-1RA and MIP-1 alpha, is stimulated. The combined action of IFN-alpha on paracrine expression of cytokines suggests an indirect antihematopoietic effect, which might contribute to its clinical activity in MPD.
Leuk Lymphoma 1996 Sep
PMID:Influence of interferon-alpha on cytokine expression by the bone marrow microenvironment--impact on treatment of myeloproliferative disorders. 895 83

Adult T cell leukemia (ATL) cells show a mature helper-inducer T cell phenotype and are thought to secrete many kinds of cytokines in vivo, complicating the clinical features in these patients. In an attempt to specify the cytokines produced by ATL cells, we measured the cytokine concentration in the culture supernatants of three ATL cell lines, all of which were confirmed to be true peripheral blood ATL cell in origin. All these cell lines showed the same cytokine production profile, secreting IL1-alpha, IL1-beta, LD78(MIP-l alpha), TNF-alpha, IFN-gamma, and GM-CSF, but not secreting IL-1 alpha, IL-1 beta, IL-1 receptor antagonist (IL-1 Ra), IL-4, IFN-alpha, and G-CSF irrespective of the stimulatory agents used. Such limited cytokine production may indicate the specific origin of ATL cells within the helper-inducer T cell subtypes. Moreover, these results explain some of the unusual clinical features of ATL patients.
Leuk Lymphoma 1996 May
PMID:Features of the cytokines secreted by adult T cell leukemia (ATL) cells. 917 9

Kaposi's sarcoma (KS) is a skin disease characterised by spindle cells proliferation and neovascularisation which, in 1994, was associated with a new Gammaherpesvirinae, named human herpesvirus 8 (HHV8). The HHV8 genome, containing more than 140 kilobases, includes genes encoding structural proteins and enzymes, and some homologues to cellular genes which could have been captured in host cells during viral evolution. Several HHV8 proteins interfere with the host cellular cycle either by inhibiting apoptosis or by positive regulation of the cell cycle (viral cyclin or v-cyclin, v-bcl-2, v-FLIP). HHV8 also contains potential oncogenes (v-IRF and v-GPCR, which promote angiogenesis, in particular the secretion of VEGF) as well as homologues of human cytokines and chemokines (v-IL6, v-MIP). HHV8 is clearly associated with KS, multicentric Castleman disease and primary effusion lymphoma. Most of the cells are infected by latent virus, resulting in persistent infection of the lesions. Only a minority of infected cells yield infectious viral particles, and their role in the development of KS and other associated diseases has not been clearly established. The molecular mechanisms and cofactors involved in the physiopathology of this infection have yet to be identified.
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PMID:[Kaposi's disease and HHV8: a new model of virus-induced tumorigenesis]. 1096 29

The molecular and genetic events that contribute to the genesis and progression of cutaneous malignant melanoma are poorly understood, attributable in large part to the different genetic alterations accompanying tumorigenesis. Inhibitor of kinase 4a (INK4a) is often inactivated in families with hereditary melanoma. Loss of INK4a/alternate reading frame (ARF) in mice is associated with increased incidence of other tumors such as lymphoma and fibrosarcoma. However, the incidence of melanoma in INK4a/ARF-deficient mice is very low. Our previous studies have revealed that the CXC chemokine, CXCL1, is overexpressed in human malignant melanoma cells and is linked to transformation of immortalized murine melanocytes. To study the direct role of CXCL1 on the genesis of primary melanoma lesions, transgenic mouse lines were established that express the murine homologue of CXCL1, murine macrophage inflammatory protein 2 (MIP-2), under the transcriptional control of the tyrosinase promoter/enhancer (Tyr-MIP-2) in the mice that were deficient or not deficient for INK4a/ARF. Strong MIP-2 immunoreactivity was associated with pigmented melanocytes in the hyperproliferative hair follicles in the Tyr-MIP-2 transgenic mice, and the level of MIP-2 expression was similar in both INK4a/ARF heterozygous or wild-type mice. After treatment of mice with 7,12-dimethylbenz(a)anthracene, cutaneous melanomas formed in 12% (17/145) of the Tyr-MIP-2 transgene-positive mice, whereas only 2% (3/146) of the Tyr-MIP-2 transgene-negative mice developed melanoma. When melanocytes cultured from MIP-2 transgenic mice null for INK4a/ARF were transplanted into nude mice, melanoma formation occurred in 83% (10/12) of the cases with a latency period of 3 months. However, no melanoma lesions arose in nude mice injected with INK4a/ARF -/- melanocytes, which did not express the MIP-2 transgene. Our results demonstrate that constitutive expression of MIP-2 in INK4a/ARF-deficient melanocytes facilitates formation of malignant melanoma.
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PMID:Induction of melanoma in murine macrophage inflammatory protein 2 transgenic mice heterozygous for inhibitor of kinase/alternate reading frame. 1171 44

Chemokines are cytokines which induce chemotaxis on many cell types, thus regulating cell migration within inflammatory and allergic sites, and leucocyte homing. Also, they play a crucial role in inflammatory and tumor-associated angiogenesis, as well as in tumor progression. Chemokines are grouped into: 1) alpha or CXC; 2) beta or CC; 3) gamma or C; 4) delta or CX3C molecules. Each of them recognizes one or more cell surface receptors, named CXCR, CCR, XCR, CX3CR respectively, according to the corresponding subfamily. Many chemokines have been identified within tumor tissues, as a secretory product of tumor cells and/or inflammatory cells. The CXC chemokines (such as IL-8, IP10, Mig, SDF-1 alpha) or CC chemokines (such as MCP-1, MIP-1 alpha, eotaxin, RANTES) have been frequently harvested from tumor tissues or the biological fluids of patients. Some chemokines inhibit tumor growth and progression by activating immunocompetent cytolytic cells or inhibiting tumor-associated angiogenesis. In contrast, other chemokines induce tumor progression by interacting with the specific receptor expressed on the tumor cells and hence by activating chemotaxis and secretion of proteolytic enzymes, or by inducing angiogenesis and metastatic spreading. Sometimes neoplastic cells express chemokine receptors which are not expressed on their normal counterpart. Data from this lab show the CXCR3 expression by cells from lymphoproliferative diseases, such as multiple myeloma and lymphoma, and the stimulation of an invasive phenotype following interaction with specific chemokines.
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PMID:[Chemokines and tumors]. 1248 85

Several chemokines have been shown to regulate cellular apoptosis following discrete stimuli. It was previously demonstrated that the CC chemokine CCL1 (I-309) rescues thymic lymphoma cells from apoptosis by unknown mechanisms. The aim of our study was to characterize the role of the CC chemokine receptor 8 (CCR8), the only described receptor for CCL1, in the rescue of murine thymic lymphoma cells and murine thymocytes from dexamethasone (dex)-induced apoptosis. We show here that the CCR8-restricted agonist Kaposi sarcoma-associated herpesvirus-encoded chemokine viral macrophage-inflammatory protein-1 (vMIP-1) rescues thymic lymphoma cells from dex-induced apoptosis, similar to CCL1, and that such rescue is extracellular-regulated kinase-dependent. Although it has been hypothesized that the rescuing effect of CCL1 from apoptosis could be CCR8-mediated, here, we formally demonstrate the role of such receptor as its selective antagonist encoded by the MC148 gene of molluscum contagiosum virus MC148/vMCC-I inhibits v-MIP-1- and CCL1-induced rescue activity. In addition, CCR8 ligands inhibit dex-induced apoptosis of murine thymocytes with potential implications for thymic selection.
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PMID:The chemokine receptor CCR8 mediates rescue from dexamethasone-induced apoptosis via an ERK-dependent pathway. 1252 79

Multiple myeloma (MM) is a plasma cell malignancy localized in the bone marrow (BM) and characterized by a high capacity for bone destruction. Almost all patients with MM have early osteolytic lesions, which result mainly from increased bone resorption related to stimulation of osteoclast recruitment and activity in the immediate vicinity of myeloma cells. The recent discovery of Osteoprotegerin (OPG) and the subsequent identification of its ligand RANKL have provided new insights in the regulation of osteoclastogenesis. The ratio OPG/RANKL is critical for the regulation of bone remodeling maintaining the balance between osteoblastic and osteoclastic activity. This review summarizes the new concept that myeloma cells induce in bone environment an imbalance in the OPG/RANKL system responsible for osteolysis observed in patients. Indeed, myeloma cells increase in bone environment the expression of the potent osteoclastogenic factor RANKL and decrease the osteoprotective factor OPG production. Biological mechanisms involved in these processes are discussed. Furthermore, the chemokines MIP-1alpha and MIP-1beta belonging to the RANTES family are potent osteoclastogenic factors produced by myeloma cells and participate in myeloma-associated bone disease. These data open new avenues for the treatment of bone disease in MM and highlight the promising therapeutical interest of RANKL inhibitors (OPG and RANK-Fc) and MIP-1 inhibitors in the management of myeloma-associated osteolysis, besides bisphosphonates.
Leuk Lymphoma 2003 Sep
PMID:New insights in myeloma-induced osteolysis. 1456 45


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