Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cell-surface receptor for hyaluronic acid, CD44, is expressed by both normal and malignant cells. Numerous CD44 isoforms have recently been identified that are derived by alternative ribonucleic acid splicing. The expression of some CD44 isoforms has been shown to be involved in tumor progression and metastatic spread in a rat carcinoma model and in human carcinomas. In the present study, CD44 isoform expression was evaluated by reverse transcriptase-polymerase chain reaction (PCR) analysis in frozen sections derived from three samples of normal brain tissue and from 40 brain tumors, including samples of glioblastoma multiforme, anaplastic astrocytoma, low-grade astrocytoma, cerebral primitive neuroectodermal tumor, medulloblastoma, metastatic colon carcinoma, and metastatic melanoma. Normal brain tissue adjacent to the tumors was also examined in 14 of 18 glioblastomas. In all normal brain and tumor samples, with the exception of metastases from colon carcinoma, PCR analysis demonstrated one prominent product that corresponded to the CD44H hematopoietic form of CD44. Metastases from colon carcinoma demonstrated two prominent PCR amplification products corresponding to CD44H and CD44R1. These results suggest that CD44H is the predominant isoform of this protein in normal human brain tissue and in human neuroectodermal tumors of varying degrees of malignancy. The ability of CD44H to mediate tumor cell motility and invasiveness (in contrast to CD44R1) suggests that the CD44 alternative splicing pattern of neuroectoderm-derived tumors may enhance their local biological aggressiveness and intracerebral spread. The lack of expression of larger molecular weight CD44 variants by primary brain tumors may also partially explain why these tumors rarely metastasize to distant sites.
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PMID:Alternative RNA splicing of the hyaluronic acid receptor CD44 in the normal human brain and in brain tumors. 753 36

CD44 is a glycosylated adhesion molecule which may undergo alternative splicing of 10 possible exons to generate variant isoforms. A number of CD44 variant isoforms expressed by tumor cells have been correlated with metastatic and proliferative behavior. In this study, we have characterized CD44 isoform expression on three prostate cancer cell lines: ALVA-31, PPC-1, and LNCaP. Using reverse transcriptase-polymerase chain reaction, we have found that ALVA-31 and PPC-1 cells express multiple CD44 isoforms, including CD44s (standard form), CD44E (epithelial form), and an exon 14-containing form. In addition, two smaller forms have been detected: one using an alternative donor splice site within exon 5, and a novel form omitting exon 5 entirely. The CD44 isoforms expressed by ALVA-31 and PPC-1 cells appear to be preferentially located on the cell surface. By contrast, LNCaP cells do not express any of the CD44 forms at the RNA or protein level. Both PPC-1 and ALVA-31 cells display tumorigenesis and invasiveness in nude mice, whereas LNCap cells exhibit a less malignant phenotype, suggesting a correlation between CD44 variant (CD44v) expression and aggressive prostate tumor behavior. Functional characterization reveals that CD44 mediates prostate cell adhesion to extracellular hyaluronic acid (HA). In addition, the CD44 cytoplasmic domain binds specifically to ankyrin, a membrane cytoskeletal protein. Double immunofluorescence labeling and confocal microscopic analyses indicate that HA binding induces the HA receptor (i.e., CD44) to form capped structures. Importantly, intracellular ankyrin is preferentially accumulated underneath HA receptor-capped structures. These results suggest that cytoskeletal proteins such as ankyrin are closely associated with CD44-mediated signaling events induced by HA. Finally, HA-mediated transmembrane interactions between CD44 isoforms and cytoskeletal proteins (i.e. ankyrin) may play a pivotal role in regulating tumor cell behavior during human prostate cancer development.
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PMID:Interaction of CD44 variant isoforms with hyaluronic acid and the cytoskeleton in human prostate cancer cells. 754 57

Among glycosaminoglycans, dermatan sulfate (DS) is the strongest inhibitor of DNA synthesis in adult rat hepatocytes in primary culture stimulated with insulin and epidermal growth factor. Hyaluronate also inhibited DNA synthesis, whereas chondroitin-6 sulfate, 4-sulfate or heparin had no effect on DNA synthesis in hepatocytes. Analysis of growth regulatory factors in hepatocyte culture medium treated with DS revealed that interleukin-1 (IL-1) was released into the medium. IL-1 beta mRNA was detected in DS-treated hepatocytes by reverse transcriptase-polymerase chain reaction, but not in untreated hepatocytes. For a marked inhibition of DNA synthesis, more than 10 hr of exposure to DS before cultured hepatocytes started DNA synthesis, was required. Similarly, more than 10 hr was required after the addition of DS before IL-1 beta mRNA was detected. These findings suggest that DS in the medium induced the production of IL-1 beta which, in turn, reduced DNA synthesis in hepatocytes.
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PMID:Release of interleukin-1 beta by dermatan sulfate suppresses hepatocyte growth. 866 99

Expression of CD44 and of specific splice-variants of CD44 has been causally related to metastatic behaviour in a variety of carcinomas and lymphomas. To elucidate whether, in principle, similar splice-variants could be involved in glioma cell invasion we examined the expression of CD44 and its splice-variants in a series of 38 primary human brain tumors (28 astrocytomas, WHO grade I-III and 10 glioblastomas, WHO grade IV) and in cell lines derived from 9 glioblastomas. All brain tumors examined showed strong immunoreactivity for an N-terminal epitope present on all CD44 isoforms known. Using a polyclonal antiserum raised against the complete sequence encoded by variant exons v3 to v10, CD44 splice-variants could be detected irrespective of the grade of malignancy in many of the tumor samples at a low level and often restricted to only a few clustered tumor cells. Thus, the N-terminal epitope probably indicates the presence of the smallest and most ubiquitous isoform CD44s. Interestingly, all glioblastomas expressed CD44 variants whereas expression in astrocytomas WHO grade I, II, and III could only be detected in about half of the tumor samples. Using reverse transcriptase-PCR we were able to detect different CD44 splice-variants in the glioblastoma cell lines and in cultured primary astrocytic cells. Glioblastoma cells analyzed by flow cytometry showed the expected binding capacity for hyaluronic acid which could be increased twofold after pretreatment with hyaluronidase. The results presented show that there is low expression of CD44 variants in human tumors of astrocytic origin. Expression of CD44 and its splice-variants could contribute to the migration capacity of neoplastic astrocytes, and may be considered as a target for new diagnostic and therapeutic approaches in the clinical management of brain tumors.
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PMID:Expression of variant CD44 epitopes in human astrocytic brain tumors. 875 Jan 82

In this study we have found that endothelial cells from different origins all contain a CD44-related transmembrane glycoprotein, named GP116. Using a bovine aortic endothelial cell line and a standard pulse-chase protocol, we show that GP116 is synthesized as a 52-kDa nascent polypeptide precursor (p52) which is processed to GP116 as follows, p52 --> p63/65 --> p82 --> p100 --> GP116. GP116 contains approximately 8 N- and approximately 11 O-linked oligosaccharide chains (but lacks glycosaminoglycans) and interacts directly with the cytoskeletal protein, ankyrin, both in vitro (Kd approximately 1.2 nM) and in vivo. The results of GP116 amino acid composition, reverse transcriptase-polymerase chain reaction, Southern blot, Northern blot, cloning, and sequence analyses indicate that endothelial cells express this new CD44 variant that contains an exon having significant homology with human CD44 exon 14 (ex14/v10). GP116, designated as CD44 (ex14/v10), has been shown to be a major hyaluronic acid (HA) receptor (Kd approximately 0.5-0.8 nM) responsible for cell adhesion. Most importantly, we have found that the interaction between CD44(ex14/v10) and HA or a small fragment of HA (10-15 disaccharide units) induces a mitogenic response in endothelial cells. These findings suggest that this CD44 variant plays an important role in regulating endothelial cell proliferation.
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PMID:The cell adhesion molecule, GP116, is a new CD44 variant (ex14/v10) involved in hyaluronic acid binding and endothelial cell proliferation. 879 16

CD44 is a major receptor for hyaluronic acid, which is the most frequent route of malignant glioma invasion. Multiple isoforms of CD44 are generated by alternative mRNA splicing. We have examined differential expression of CD44 variant isoforms (CD44vs) during dibutyryl cyclic AMP (dbcAMP)/theophylline-induced differentiation of human glioma A172 cells using reverse transcriptase-polymerase chain reaction (RT-PCR). Treatment of cells with dbcAMP and theophylline caused decreased expression of all CD44 isoforms after 24 h. The CD44 standard form was observed to return to the unstimulated level after 72 h, whereas the variant isoforms, CD44 8v-10v and 10v, remained at the low level after 24-72 h. Changes of CD44vs were correlated with the level of expression of c-jun. These results suggested that the expression patterns of CD44vs might correlate with cellular differentiation in human glioma cells.).
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PMID:Suppressed expression of CD44 variant isoforms during human glioma A172 cell differentiation induced by cyclic AMP. 880 27

CD44 is a cell surface glycoprotein involved in cell migration and cell docking in target organs via interactions with various ligands, including hyaluronic acid (HA), which is the principal ligand of this receptor. Alternative splicing generates many isoforms of CD44, including standard CD44 (CD44s) and CD44 variants (CD44v). LB T-cell lymphoma, which predominantly expresses CD44s, acquires additional CD44v and HA binding capacity after activation with phorbol ester. The HA9 cell line, isolated from parental LB cells, expresses CD44v and constitutively binds HA. Downregulation of CD44v isoforms of HA9 cells, by CD44v specific antisense inhibited their ability to bind HA, indicating that CD44v, rather than CD44s, is associated with the activation status of this molecule. Using the reverse transcriptase polymerase chain reaction, we found that LB cells after infiltrating spleen and lymph nodes of BALB/c mice, contain an enriched repertoire of CD44v, implying that the metastatic cells acquired the activated form of this receptor.
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PMID:The CD44 receptor of the mouse LB T-cell lymphoma: analysis of the isoform repertoire and ligand binding properties by reverse-transcriptase polymerase chain reaction and antisense oligonucleotides. 1075 21

Hyaluronic acid (HA), a glycosaminoglycan, regulates cell adhesion and migration. Hyaluronidase (HAase), an endoglycosidase, degrades HA into small angiogenic fragments. Using an enzyme-linked immunosorbent assay-like assay, we found increased HA levels (3-8-fold) in prostate cancer (CaP) tissues when compared with normal (NAP) and benign (BPH) tissues. The majority ( approximately 75-80%) of HA in prostate tissues was found to exist in the free form. Primary CaP fibroblast and epithelial cells secreted 3-8-fold more HA than respective NAP and BPH cultures. Only CaP epithelial cells and established CaP lines secreted HAase and the secretion increased with tumor grade and metastasis. The pH activity profile and optimum (4.2; range 4.0-4.3) of CaP HAase was identical to the HYAL1-type HAase present in human serum and urine. Full-length HYAL1 transcript and splice variants were detected in CaP cells by reverse transcriptase-polymerase chain reaction, cloning, and sequencing. Immunoblotting confirmed secretion of a approximately 60-kDa HYAL1-related protein by CaP cells. Immunohistochemistry showed minimal HA and HYAL1 staining in NAP and BPH tissues. However, a stromal and epithelial pattern of HA and HYAL1 expression was observed in CaP tissues. While high HA staining was observed in tumor-associated stroma, HYAL1 staining in tumor cells increased with tumor grade and metastasis. The gel-filtration column profiles of HA species in NAP, BPH, and CaP tissues were different. While the higher molecular mass and intermediate size HA was found in all tissues, the HA fragments were found only in CaP tissues. In particular, the high-grade CaP tissues, which showed both elevated HA and HYAL1 levels, contained angiogenic HA fragments. The stromal-epithelial HA and HYAL1 expression may promote angiogenesis in CaP and may serve as prognostic markers for CaP.
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PMID:Stromal and epithelial expression of tumor markers hyaluronic acid and HYAL1 hyaluronidase in prostate cancer. 1127 12

Polymorphonuclear cells (PMNs) contribute to the initiation and progression of the immune response by mediating cytotoxicity, phagocytosis, and cytokine secretion. Because CD44 serves as a cytotoxic-triggering molecule on PMNs, it was hypothesized that it could also trigger cytokine production. In this study, the effect of anti-CD44 antibodies on interleukin-6 (IL-6) production in human PMNs was assessed. By using a reverse transcriptase-polymerase chain reaction, it was shown that PMNs stimulated with a mouse monoclonal or a rabbit polyclonal F(ab)(2) anti-CD44 transcribe IL-6 messenger RNA. A similar effect was obtained when an anti-CD44 antibody was replaced with hyaluronic acid (HA). Kinetic studies showed that anti-CD44 and HA induced IL-6 gene transcription, initiated 3 hours after stimulation, peaked between 12 and 24 hours, and disappeared after 48 hours. Analogous results were achieved when secreted IL-6 protein was measured by enzyme-linked immunosorbent assay in the PMN culture supernatants. To characterize which metabolic pathways regulated CD44-dependent IL-6 production in PMNs, an RNA polymerase inhibitor, actinomycin D, and 2 protein kinase inhibitors, such as genistein and staurosporine, were tested. Actinomycin D and genistein blocked IL-6 production, whereas staurosporine did not, suggesting that CD44-dependent IL-6 production requires gene transcription and tyrosine kinase activity. Furthermore, the relationship between CD44 and cytokines that affect PMN function, including interferon gamma (IFNgamma) and IL-2, was investigated. Without CD44 cross-linking, IFNgamma did not trigger IL-6 production. However, on CD44 cross-linking, IFNgamma produced a strong synergistic effect on IL-6 syntheses in human PMNs. (Blood. 2001;97:3621-3627)
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PMID:CD44 ligation on peripheral blood polymorphonuclear cells induces interleukin-6 production. 1136 59

Hyaluronan or hyaluronic acid (HA) is a normal component of mammalian follicular, oviduct, and uterine fluids. Granulosa and expanding cumulus cells secrete large amounts of HA, and when HA is added in maturation and culture media, it improves the developmental potential of oocytes and embryos. HA regulates gene expression, signaling, proliferation, motility, adhesion, and morphogenesis. Many of these biological activities of HA are mediated through binding to the receptor for HA-mediated motility/intracellular HA-binding protein (RHAMM/IHABP). We evaluated the presence and dynamics of RHAMM/IHABP mRNA and protein expression in different stages of in vitro-produced bovine embryos using quantitative reverse transcriptase-real time-polymerase chain reaction and immunohistochemistry. We also analyzed the effects of different culture systems on the relative abundance of RHAMM/IHABP transcripts. RHAMM/IHABP mRNA levels decreased from the 2-cell to the 16-cell stage, increased again at the morula stage, and reached their highest level at the expanded blastocyst stage. RHAMM/IHABP mRNA abundance was significantly (P < 0.05) lower in embryos recovered in serum-containing medium than in embryos from serum-free media. Immunohistochemistry revealed the presence of RHAMM/IHABP first in 8-cell stages. Whereas RHAMM staining in 8-cell and morula stages was intense, it was weaker in blastocysts. Embryonic secretion of HA increased from the 2-cell stage until the 8-cell stage and then decreased in 16-cell embryos. After this, HA secretion increased in expanded and hatched blastocyst stages. These data suggest that the positive effects of HA on in vitro-produced bovine embryos may be mediated at least in part by RHAMM/IHABP.
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PMID:Developmental regulation of hyaluronan-binding protein (RHAMM/IHABP) expression in early bovine embryos. 1249 96


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