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)

LD78 is a small secreted protein that has a sequence similar to a number of other polypeptides, including murine macrophage inflammatory protein 1 alpha (MIP-1 alpha), interleukin 8 (IL-8), Act-2, monocyte chemoattractant protein 1 (MCP-1), and others. These polypeptides are members of a novel cytokine superfamily that is involved in the inflammatory response, wound healing, hematopoiesis, and tumorigenesis. Specific receptors for purified clonal LD78 protein were measured using four cell lines (HL-60, U937, Jurkat, and MJ). 125I-labeled recombinant LD78 bound most efficiently to U937 cells. We therefore characterized the receptors as being on the surface of U937 cells. Binding reached an equilibrium after incubation for 60 min at 4 degrees C. Scatchard analysis showed that there were two classes of binding sites on U937 cells, high affinity sites (Kd = 5.3 x 10(-9) M) and low affinity sites (Kd = 9.3 x 10(-8) M), with the average number of binding sites per cell being approximately 30,000 and approximately 90,000, respectively. These receptors for LD78 were distinct from the receptors for gamma-IFN and for IL-8. SDS-PAGE analysis of chemically crosslinked 125I-labeled LD78 receptor complexes identified a single band of 52 kDa. The ability to detect specific LD78 receptors should prove valuable in efforts to molecularly clone these receptors and to dissect the biological actions of LD78.
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PMID:Identification and characterization of specific receptors for the LD78 cytokine. 151 Nov 63

The pX gene of human T-cell leukemia virus type I (HTLV-I) is known to be a potent transactivator of the viral gene and the host genes which are important for cell proliferation in vitro. It has been reported that various diseases occur in transgenic mice harboring either tax, pX, or env-pX gene, such as mesenchymal tumor, neurofibroma, thymic atrophy, muscle degeneration, exocrinopathy and arthropathy. We previously demonstrated that rat but not mouse CD4 positive T cells could be easily infected and immortalized by HTLV-I and infectious transmission of HTLV-I induced HAM/TSP-like myelopathy in WKAH rats after long incubation periods of 16 months. These observations prompted us to produce a series of transgenic rats that expressed the pX gene products under the control of mouse H-2Kd promotor in order to evaluate further the biological and pathological function of the pX gene in vivo. In various tissues of pX transgenic rats (pX rats), pX mRNA was constitutively expressed irrespective of age. PX rats developed mammary tumors with massive infiltration by neutrophils as early as 9 months of age. Pathological and immunohistochemical examination revealed that the tumors were undifferentiated carcinomas of the mammary gland origin. They were transplantable into pX rats, but not into normal syngenic rats. High levels of mRNA expression of not only the pX transgene but also the host genes such as Gro (melanoma growth-stimulatory activity/KC), MIP-2 (macrophage inflammatory protein-2) and IL-1 alpha were demonstrated in the tumor tissues. Gro and MIP-2 which were known as IL-8 families were likely to be produced by tumor cells and appeared to be responsible for neutrophil infiltration in the tumor tissues. Lastly, pX rats described here appear to be suitable animal models for elucidating mechanisms involved in the tumorigenesis and the transactivation of the cellular genes by HTLV-I, especially by the pX gene products in vivo.
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PMID:[Pathological and molecular analyses of mammary tumors induced in HTLV-I pX transgenic rats]. 792 76

In two lines of transgenic rats (pX rats) from WKAH and F344 strains and carrying the HTLV-I pX gene under control of the mouse H-2Kd promoter, mammary carcinomas developed predominantly in females starting at about 5 months of age. The incidence of the tumor reached about 40% when the rats were 12 months old. Histology of the tumor was undifferentiated carcinoma with massive infiltration of granulocytes into the tumor tissue. Systemic granulocytosis and hepato-splenomegaly due to extramedullary granulocytopoiesis were seen in pX rats and nude mice bearing pX mammary tumor. mRNAs of both pX and host genes, Gro and MIP-2, which are granulocyte chemoattractants of the IL-8 family, were highly expressed in the tumor tissue. Since expression and point mutation of several oncogenes and anti-oncogene, related with mammary carcinomas, were not demonstrated, hitherto unidentified novel oncogenic pathways may be transactivated by the pX transgene in these pX rats. pX mammary carcinoma cell lines, which have similar characteristics to the primary tumor, were established and the cells underwent apoptosis under the serum deprived conditions. The pX rats and the pX mammary carcinomas appear to be suitable models for analyses of HTLV-I pX oncogenesis and immune pathogenesis in vivo and in vitro.
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PMID:HTLV-I pX transgenic rats: development of cytokine-producing mammary carcinomas and establishment of the pX mammary carcinoma cell lines. 920 2

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

The CXC chemokine, CXCL1 (melanoma growth-stimulatory activity/growth-regulated protein alpha), plays a major role in inflammation, angiogenesis, tumorigenesis, and wound healing. Recently, chemokines have been extensively related to cellular transformation, tumor growth, homing, and metastasis. CXCL1 and its mouse homologue MIP-2 have been shown to be involved in the process of tumor formation. When chemokines such as CXCL1 and CXCL8 (IL-8) become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. This up-regulation of chemokines has been attributed to constitutive activation of NF-kappaB. The constitutive NF-kappaB activation is an emerging hallmark in various types of tumors including breast, colon, pancreatic, ovarian, as well as melanoma. Previous findings from our laboratory and other laboratories have demonstrated the role of endogenous activation of NF-kappaB in association with enhanced metastatic potential of malignant melanoma cells and suggest that targeting NF-kappaB may have potential therapeutic effects in clinical trials. An important step in this direction would be to delineate the important intracellular pathways and upstream kinases involved in up-regulation of NF-kappaB in melanoma cells. In this review, the signaling pathways involved in the disregulation of NF-kappaB and chemokine expression are discussed.
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PMID:Role of CXCL1 in tumorigenesis of melanoma. 1210 Dec 57

Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras(G12D) alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.
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PMID:K-ras activation generates an inflammatory response in lung tumors. 1628 13

CXCL8, a ligand for the chemokine receptor CXCR2, was recently reported to be a transcriptional target of Ras signaling, but its role in Ras-induced tumorigenesis has not been fully defined. Here, we investigated the role of KC and MIP-2, the murine homologues of CXCL8, in Kras(LA1) mice, which develop lung adenocarcinoma owing to somatic activation of the KRAS oncogene. We first investigated biological evidence of CXCR2 ligands in Kras(LA1) mice. Malignant progression of normal alveolar epithelial cells to adenocarcinoma in Kras(LA1) mice was associated with enhanced intralesional vascularity and neutrophilic inflammation, which are hallmarks of chemoattraction by CXCR2 ligands. In in vitro migration assays, supernatants of bronchoalveolar lavage samples from Kras(LA1) mice chemoattracted murine endothelial cells, alveolar inflammatory cells, and the LKR-13 lung adenocarcinoma cell line derived from Kras(LA1) mice, an effect that was abrogated by pretreatment of the cells with a CXCR2-neutralizing antibody. CXCR2 and its ligands were highly expressed in LKR-13 cells and premalignant alveolar lesions in Kras(LA1) mice. Treatment of Kras(LA1) mice with a CXCR2-neutralizing antibody inhibited the progression of premalignant alveolar lesions and induced apoptosis of vascular endothelial cells within alveolar lesions. Whereas the proliferation of LKR-13 cells in vitro was resistant to treatment with the antibody, LKR-13 cells established as syngeneic tumors were sensitive, supporting a role for the tumor microenvironment in the activity of CXCR2. Thus, high expression of CXCR2 ligands may contribute to the expansion of early alveolar neoplastic lesions induced by oncogenic KRAS.
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PMID:High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. 1661 42

Overexpression of fibroblast growth factor receptor 3 (FGFR3) is a hallmark of t(4;14) multiple myeloma (MM). To dissect the mechanism of FGFR3 oncogenesis in MM, we used 3 FGFR selective kinase inhibitors-CHIR258, PD173074, and SU5402-and FGFR3-specific siRNA to modulate FGFR3 activity. Conversely, the ligand FGF was used to stimulate FGFR3 function in human MM cells. The transcriptional response to FGFR3 modification was recorded, and gene expression changes common to all 5 modifiers were documented. Ten genes were commonly regulated. Macrophage inflammatory protein-1 alpha (MIP-1alpha) was the single most differentially altered gene. MIP-1 alpha promoter function, gene expression, and protein secretion were each down-regulated following inhibition of FGFR3 signaling. Down-regulation of MIP-1 alpha was not, however, observed following FGFR3 inhibition in MM cells with RAS mutations implicating RAS-MAPK in MIP-1 alpha regulation. As confirmation, inhibition of ERK1 also down-regulated MIP-1 alpha in FGFR3 inhibitor-resistant cells harboring RAS mutations. MIP-1 alpha is implicated in the survival and proliferation of MM cells and the pathogenesis of MM bone disease. Our observation is the first to directly link an initiating IgH translocation not only to MM-cell growth and survival but also to the disease-associated bone disease.
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PMID:MIP-1alpha (CCL3) is a downstream target of FGFR3 and RAS-MAPK signaling in multiple myeloma. 1684 42

Arrestins are adaptor/scaffold proteins that complex with activated and phosphorylated G protein-coupled receptor to terminate G protein activation and signal transduction. These complexes also mediate downstream signaling, independently of G protein activation. We have previously shown that beta-arrestin-2 (betaarr2) depletion promotes CXCR2-mediated cellular signaling, including angiogenesis and excisional wound closure. This study was designed to investigate the role of betaarr2 in tumorigenesis using a murine model of lung cancer. To that end, heterotopic murine Lewis lung cancer and tail vein metastasis tumor model systems in betaarr2-deficient mice (betaarr2(-/-)) and control littermates (betaarr2(+/+)) were used. betaarr2(-/-) mice exhibited a significant increase in Lewis lung cancer tumor growth and metastasis relative to betaarr2(+/+) mice. This correlated with decreased number of tumor-infiltrating lymphocytes but with elevated levels of the ELR(+) chemokines (CXCL1/keratinocyte-derived chemokine and CXCL2/MIP-2), vascular endothelial growth factor, and microvessel density. NF-kappaB activity was also enhanced in betaarr2(-/-) mice, whereas hypoxia-inducible factor-1alpha expression was decreased. Inhibition of CXCR2 or NF-kappaB reduced tumor growth in both betaarr2(-/-) and betaarr2(+/+) mice. NF-kappaB inhibition also decreased ELR(+) chemokines and vascular endothelial growth factor expression. Altogether, the data suggest that betaarr2 modulates tumorigenesis by regulating inflammation and angiogenesis through activation of CXCR2 and NF-kappaB.
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PMID:Depletion of beta-arrestin-2 promotes tumor growth and angiogenesis in a murine model of lung cancer. 1839 Jul 55

Alveolar macrophages play an important role in the distribution, clearance and inflammatory reactions after particle inhalation, which may influence long-term events such as fibrosis and tumorigenesis. The objectives of the present study were to investigate the early inflammatory events after plutonium oxide inhalation in rats and involvement of alveolar macrophages. Lung changes were studied from 3 days to 3 months after inhalation of PuO2 of different isotopic compositions (70% or 97% 239Pu) and initial lung deposits (range 2.1 to 43.4 kBq/rat). Analyses of bronchoalveolar lavages showed early increases in the numbers of granulocytes, lymphocytes and multinucleated macrophages. The activation of macrophages was evaluated ex vivo by measurement of inflammatory mediator levels in culture supernatants. TNF-alpha and chemokine MCP-1, MIP-2 and CINC-1 production was elevated from 7 days after inhalation and remained so up to 3 months. In contrast, IL-1beta, IL-6 and IL-10 production was unchanged. At 6 weeks, pulmonary macrophage numbers and activation state were increased as observed from an immunohistochemistry study of lung sections with anti-ED1. Similarly, histological analyses of lung sections also showed evidence of inflammatory responses. In conclusion, our results indicate early inflammatory changes in the lungs of PuO2-contaminated animals and the involvement of macrophages in this process. A dose-effect relationship was observed between the amount of radionuclide inhaled or retained at the time of analysis and inflammatory mediator production by alveolar macrophages 14 days after exposure. For similar initial lung deposits, the inflammatory manifestation appears higher for 97% 239Pu than for 70% 239Pu.
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PMID:Activation of alveolar macrophages after plutonium oxide inhalation in rats: involvement in the early inflammatory response. 1895 59


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