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:3.2.1.36 (hyaluronidase)
4,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We recently cloned the major hyaluronidase of human plasma, which we termed HYAL1. All hyaluronidase activity could be purified from human urine on an anti-HYAL1 monoclonal antibody column. However, urine contains two hyaluronidases of 57 kDa and 45 kDa, whereas plasma only contains the 57 kDa activity. Microsequencing confirmed that both urinary isozymes have N-termini identical to plasma hyaluronidase, but a second N-terminus was found in the smaller isozyme, apparently derived from the terminal 25 amino acids of HYAL1, at the C-terminus. The two polypeptides of the 45 kDa isozyme resulting from endoproteolytic cleavage of the 57 kDa isoform are presumably linked by disulfide bonds. Sperm contains two isozymes of the testicular hyaluronidase, PH-20, and the lower molecular weight isozyme is believed to be an endoproteolytically processed form of the larger protein. Analogously to PH-20, the smaller isozyme of HYAL1 is likely to be a proteolytically processed product of the larger isozyme.
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PMID:Purification and microsequencing of hyaluronidase isozymes from human urine. 940 39

We recently cloned and expressed the major hyaluronidase activity from human plasma, HYAL1, and found that the protein is 40% identical to the testicular hyaluronidase, PH-20. The HYAL1 mRNA sequence was used in a homology search of the mouse database of expressed sequence tags (dbEST). Two ESTs were obtained and, in combination with 5'RACE-PCR, were used to clone the mouse HYAL1 ortholog (Hyal1). Hyal1 codes for a protein of 462 amino acids that is 73% identical to the human sequence. Hyal1 stably expressed in human embryonic kidney cells resulted in a 20,000-fold increase of hyaluronidase activity. Sequence-tagged sites derived from the HYAL1 gene from both species were used to isolate P1 genomic clones that were used as probes for fluorescence in situ hybridization. The human gene was localized to chromosome 3p21 and the mouse gene to a syntenic region on chromosome 9F1-F2. In mouse, serum hyaluronidase polymorphism has previously been mapped by an interspecific backcross to 60 cM from the centromere of chromosome 9, which corresponds to a cytogenetic location of 9F1-F2. The mouse Hyal1 gene is therefore very likely to be responsible for the hyaluronidase polymorphism linked to this locus. We also present evidence that human HYAL1 is identical to an uncharacterized gene positionally cloned by others from chromosome 3p21.3 that is homozygously deleted in several small-cell lung carcinoma cell lines.
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PMID:The hyaluronidase gene HYAL1 maps to chromosome 3p21.2-p21.3 in human and 9F1-F2 in mouse, a conserved candidate tumor suppressor locus. 950 17

Hyaluronan (HA), a large glycosaminoglycan abundant in the extracellular matrix, is important in cell migration during embryonic development, cellular proliferation, and differentiation and has a structural role in connective tissues. The turnover of HA requires endoglycosidic breakdown by lysosomal hyaluronidase, and a congenital deficiency of hyaluronidase has been thought to be incompatible with life. However, a patient with a deficiency of serum hyaluronidase, now designated as mucopolysaccharidosis IX, was recently described. This patient had a surprisingly mild clinical phenotype, including notable periarticular soft tissue masses, mild short stature, an absence of neurological or visceral involvement, and histological and ultrastructural evidence of a lysosomal storage disease. To determine the molecular basis of mucopolysaccharidosis IX, we analyzed two candidate genes tandemly distributed on human chromosome 3p21.3 and encoding proteins with homology to a sperm protein with hyaluronidase activity. These genes, HYAL1 and HYAL2, encode two distinct lysosomal hyaluronidases with different substrate specificities. We identified two mutations in the HYAL1 alleles of the patient, a 1412G --> A mutation that introduces a nonconservative amino acid substitution (Glu268Lys) in a putative active site residue and a complex intragenic rearrangement, 1361del37ins14, that results in a premature termination codon. We further show that these two hyaluronidase genes, as well as a third recently discovered adjacent hyaluronidase gene, HYAL3, have markedly different tissue expression patterns, consistent with differing roles in HA metabolism. These data provide an explanation for the unexpectedly mild phenotype in mucopolysaccharidosis IX and predict the existence of other hyaluronidase deficiency disorders.
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PMID:Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX. 1033 81

The glycosaminoglycan hyaluronic acid (HA) and its degrading enzyme, hyaluronidase, are intricately associated with tumor metastasis and angiogenesis. HA promotes tumor cell adhesion and migration, whereas its small fragments stimulate angiogenesis. Such small HA fragments are generated from the degradation of HA by hyaluronidase. We have previously shown (V. B. Lokeshwar et al., Cancer Res., 57: 773-777, 1997) that the HA levels are elevated in the urine and tumor tissues of bladder cancer patients regardless of the tumor grade (G). The hyaluronidase levels were found to be elevated in the urine and tumor tissues of G2 and G3 bladder cancer patients. Furthermore, angiogenic HA fragments were isolated from the urine of G2/G3 bladder cancer patients, which stimulated endothelial cell proliferation, a key event in angiogenesis. In this study, we characterized the bladder tumor-derived hyaluronidase. Analysis of hyaluronidase activity in the culture-conditioned media (CM) of 11 bladder cancer cell lines, using an ELISA-like assay and a substrate (HA)-gel technique, showed that the invasive bladder cancer cell lines secrete elevated levels of a Mr approximately 60,000 hyaluronidase. Reverse transcription-polymerase chain reaction, cloning, and sequence analyses revealed the expression of an HYAL1 transcript in bladder cancer lines. HYAL1 encodes for a hyaluronidase that is present in serum. Immunoblot analysis using an anti-HYAL1 peptide IgG confirmed the presence of a Mr approximately 60,000 HYAL1-related protein in the CM of bladder cancer cell lines, in the urine specimens from G2 and G3 bladder cancer patients, and in the partially purified preparations of bladder tumor-derived hyaluronidase. No HYAL1-related protein was detected in urine specimens from normal individuals, G1 bladder cancer patients, and patients with a history of bladder cancer but no disease at the time of testing. The bladder tumor-derived hyaluronidase present in CM and partially purified preparations was found to have maximum activity at a pH range of 4.1-4.3. The identification of bladder tumor-derived hyaluronidase should help in elucidating its role in bladder tumor progression.
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PMID:Identification of bladder tumor-derived hyaluronidase: its similarity to HYAL1. 1048 99

Two new members of a family of putative hyaluronidase genes involved in glycosaminoglycan catabolism have been identified and mapped by FISH and YAC library screening to chromosome 7q31.3. One of these (HYALP1) is an expressed pseudogene with mutations in the genomic DNA and cDNA. The six members of the hyaluronidase family are grouped into two tightly linked triplets on human chromosomes 3p21.3 (HYAL1, HYAL2, and HYAL3) and 7q31.3 (HYAL4, SPAM1 (PH-20), and HYALP1). This arrangement could arise by an ancient cluster formation, followed by a more recent cluster block-duplication. All of the hyaluronidase genes have unique tissue-specific expression patterns as determined by Northern blot analysis of 23 human tissues. HYAL1, HYAL2, and HYALP1 are widely expressed, but HYAL3 is differentially expressed in bone marrow and testis, while HYAL4 is differentially expressed in placenta and skeletal muscle. SPAM1 (PH-20) was detectable only in testis by Northern blot as previously reported, but was detectable in fetal and placental cDNA libraries by PCR, suggesting a possible role for this gene during embryonic development.
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PMID:Expression analysis of six paralogous human hyaluronidase genes clustered on chromosomes 3p21 and 7q31. 1049 34

The hyaluronidase first isolated from human plasma, Hyal-1, is expressed in many somatic tissues. The Hyal-1 gene, HYAL1, also known as LUCA-1, maps to chromosome 3p21.3 within a candidate tumor suppressor gene locus defined by homozygous deletions and by functional tumor suppressor activity. Hemizygosity in this region occurs in many malignancies, including squamous cell carcinomas of the head and neck. We have investigated whether cell lines derived from such malignancies expressed Hyal-1 activity, using normal human keratinocytes as controls. Hyal-1 enzyme activity and protein were absent or markedly reduced in six of seven carcinoma cell lines examined. Comparative genomic and fluorescence in situ hybridization identified chromosomal deletions of one allele of HYAL1 in six of seven cell lines. Initial RT - PCR analyses demonstrated marked discrepancies between levels of HYAL1 mRNA and protein. Despite repeated sequence analyses, no mutations were found. However, two species of transcripts were identified when primers were used that included the 5' untranslated region. The predominant mRNA species did not correlate with protein translation and contained a retained intron. A second spliced form lacking this intron was found only in cell lines that produced Hyal-1 protein. Inactivation of HYAL1 in these tumor lines is a result of incomplete splicing of its pre-mRNA that appears to be epigenetic in nature. Oncogene (2000) 19, 870 - 877.
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PMID:HYAL1LUCA-1, a candidate tumor suppressor gene on chromosome 3p21.3, is inactivated in head and neck squamous cell carcinomas by aberrant splicing of pre-mRNA. 1070 95

Some properties of the multiple forms of human hyaluronidases in somatic tissues and in body fluids were investigated. Liver and placenta exhibited seven hyaluronidase forms when analyzed electrophoretically on a polyacrylamide-hyaluronan gel. Ovary, breast, myometrium, endometrium, skin, leukocytes and platelets displayed distinct patterns of enzymatic micropolydispersity. The most acidic forms of hyaluronidase were in synovial fluid and serum, some serum exhibited an additional basic form. Following sialidase treatment, the number of forms decreased to two in placenta, three in liver and to a broad basic form in serum. The native serum and placental hyaluronidases remained fully active after thermal inactivation but desialylated hyaluronidase was inactivated slowly in serum, and quickly in placenta suggesting a higher overall glycosylation of the plasma enzyme. Potential N-glycosylation sites were searched in the amino acid sequences of six human hyaluronidases and several hyaluronidases from different mammalian species using the PROSITE motif database. A potential N-glycosylation site (site 1) with similar tripeptide patterns was observed at the same position in human plasma (HYAL1), human lysosomes (HYAL2) and in two newly reported hyaluronidases (HYAL4 and HYALP1). The same site was also present in mouse plasma (HYAL1) and mouse lysosomes (HYAL2), and in rat lysosomes (HYAL2). This site was absent in human HYAL3 and in all sperm hyaluronidases (PH-20) studied (human, macaque, mouse, guinea pig, rabbit and fox). A second potential N-glycosylation site was observed at a location further in the polypeptide chain. This site is present in all mammalian hyaluronidase isoenzymes reported in the present study whatever the species and organ localization. The pattern at site 2 is NVT for all hyaluronidases except for hyaluronidases of lysosomal origin where it is NVS. Such conserved sites strongly suggest that they may represent actual N-glycosylation sites.
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PMID:Human hyaluronidases: electrophoretic multiple forms in somatic tissues and body fluids. Evidence for conserved hyaluronidase potential N-glycosylation sites in different mammalian species. 1098 27

Paradoxically, both hyaluronan (HA) and hyaluronidase are involved in malignant transformation and cancer progression. Their mechanisms of action, given the apparent disparities, are not understood. In many malignancies, levels of HA correlate with metastatic behavior while hyaluronidases suppress malignant progression. Hyal-1, product of one of six paralogous hyaluronidase-like sequences, is the predominant circulating hyaluronidase. HYAL1, the gene that codes for Hyal-1, is located on chromosome 3p21.3, a region containing a tumor suppressor gene. Loss of HYAL1 often correlates with tumor progression, particularly in tobacco-related cancers. In other malignancies, however, hyaluronidase functions as a tumor promoter. Testicular hyaluronidase (PH-20), used as an adjuvant in chemotherapy, is assumed to enhance drug permeability. By an unknown mechanism, hyaluronidases recruit tumor cells back into the cycling pool, making these malignancies more sensitive to chemotherapeutic drugs. Such contradictory observations might be resolved by assuming that HA and hyaluronidase are required at different times in the multiple steps that lead to malignant transformation. We have undertaken a systematic investigation of their roles in cancer progression. Here, we investigate the effect of Hyal-1 expression on cell cycle kinetics. A tumor cell line was constructed with an ecdysone-inducible promoter located upstream from the cDNA of HYAL1. Fluorescent-activated cell sorting was used to monitor cell cycle kinetics following Hyal-1 induction. Enhanced cell cycling was observed, with a 13.6% increase in S phase and 9.6% decrease in G(1)/G(0) phase cells.
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PMID:Plasma hyaluronidase (Hyal-1) promotes tumor cell cycling. 1116 12

Jaagsiekte sheep retrovirus (JSRV) can induce rapid, multifocal lung cancer, but JSRV is a simple retrovirus having no known oncogenes. Here we show that the envelope (env) gene of JSRV has the unusual property that it can induce transformation in rat fibroblasts, and thus is likely to be responsible for oncogenesis in animals. Retrovirus entry into cells is mediated by Env interaction with particular cell-surface receptors, and we have used phenotypic screening of radiation hybrid cell lines to identify the candidate lung cancer tumor suppressor HYAL2/LUCA2 as the receptor for JSRV. HYAL2 was previously described as a lysosomal hyaluronidase, but we show that HYAL2 is actually a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein. Furthermore, we could not detect hyaluronidase activity associated with or secreted by cells expressing HYAL2, whereas we could easily detect such activity from cells expressing the related serum hyaluronidase HYAL1. Although the function of HYAL2 is currently unknown, other GPI-anchored proteins are involved in signal transduction, and some mediate mitogenic responses, suggesting a potential role of HYAL2 in JSRV Env-mediated oncogenesis. Lung cancer induced by JSRV closely resembles human bronchiolo-alveolar carcinoma, a disease that is increasing in frequency and now accounts for approximately 25% of all lung cancer. The finding that JSRV env is oncogenic and the identification of HYAL2 as the JSRV receptor provide tools for further investigation of the mechanism of JSRV oncogenesis and its relationship to human bronchiolo-alveolar carcinoma.
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PMID:Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. 1129 77

The human genome contains six hyaluronidase-like genes. Three genes (HYAL1, HYAL2 and HYAL3) are clustered on chromosome 3p21.3, and another two genes (HYAL4 and PH-20/SPAM1) and one expressed pseudogene (HYALP1) are similarly clustered on chromosome 7q31.3. The extensive homology between the different hyaluronidase genes suggests ancient gene duplication, followed by en masse block duplication, events that occurred before the emergence of modern mammals. Very recently we have found that the mouse genome also has six hyaluronidase-like genes that are also grouped into two clusters of three, in regions syntenic with the human genome. Surprisingly, the mouse ortholog of HYALP1 does not contain any mutations, and unlike its human counterpart may actually encode an active enzyme. Hyal-1 is the only hyaluronidase in mammalian plasma and urine, and is also found at high levels in major organs such as liver, kidney, spleen, and heart. A model is proposed suggesting that Hyal-2 and Hyal-1 are the major mammalian hyaluronidases in somatic tissues, and that they act in concert to degrade high molecular weight hyaluronan to the tetrasaccharide. Twenty-kDa hyaluronan fragments are generated at the cell surface in unique endocytic vesicles resulting from digestion by the glycosylphosphatidyl-inositol-anchored Hyal-2, transported intracellularly by an unknown process, and then further digested by Hyal-1. The two beta-exoglycosidases, beta-glucuronidase and beta-N-acetyl glucosaminidase, remove sugars from reducing termini of hyaluronan oligomers, and supplement the hyaluronidases in the catabolism of hyaluronan.
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PMID:The six hyaluronidase-like genes in the human and mouse genomes. 1173 Dec 67


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