Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to understand the mechanism by which estrogens stimulate cell proliferation and mammary carcinogenesis, metastatic human breast cancer cell lines (MCF7, ZR75-1) were found to secrete a 52,000 dalton (52K) protein under estrogen stimulation. Following its purification to homogeneity, the 52K protein was identified as a secreted procathepsin-D-like aspartyl protease bearing mannose-6-phosphate signals. This precursor displays an in vitro autocrine mitogenic activity on estrogen-deprived MCF7 cells and is able to degrade basement membrane and proteoglycans following its autoactivation. The total protease (52K + 48K and 34K) was detected and assayed by monoclonal antibodies and was found to be highly concentrated in proliferative and cystic mastopathies. In breast cancer, its cytosolic concentration appears to be correlated more to tumor invasiveness than to hormone responsiveness. The mRNA of the 52K protease accumulates rapidly following estradiol treatment, as was shown by Northern blot analysis with cloned cDNA. The 52K cathepsin-D-like protease is the first example of a lysosomal protease induced by estrogens in cancer cells. Results obtained using different approaches suggest that two cysteinyl cathepsins are also related to cell transformation and invasiveness. It has been proposed that cathepsin-B is involved in breast cancer and metastatic melanoma, and its regulation by estrogen has been shown in the rat uterus. Cathepsin-L corresponds to the major excreted protein (MEP) whose synthesis and secretion are markedly increased by transformation of NIH 3T3 cells with Ki ras and are regulated by several growth factors. In addition to secreted autocrine growth factors and to other proteases (plasminogen activator, collagenase), lysosomal cathepsins may therefore play an important role in the process of tumor growth and invasion as long as their precursor is secreted abundantly.
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PMID:Estrogen-induced lysosomal proteases secreted by breast cancer cells: a role in carcinogenesis? 331 45

Treatment of mouse fibroblast BALB/c 3T6 cells with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate or the antipromoter retinoic acid affects the release of several glycoproteins into the medium. The phorbol ester decreases the secretion of a 180-kd and 160-kd glycoprotein and increases the release of a 38-kd glycoprotein. In contrast, retinoic acid affects these glycoproteins in the opposite way. Moreover, retinoic acid enhances the level of a 55-kd and 60-kd glycoprotein. The 180-kd and 160-kd glycoproteins appear sensitive to collagenase and after pepsin treatment are converted to bands which comigrate with collagen alpha 1 (I) and alpha 2 (I). These glycoproteins are tentatively identified as being pro alpha 1 (I) and pro alpha 2 (I). The 38-kd glycoprotein appears to comigrate with the major excreted protein. Retinoic acid appears to reduce significantly the incorporation of mannose into secreted glycoproteins whereas treatment with the phorbol ester induces an enhancement in mannose incorporation. Our results indicate that both phorbol esters and retinoids alter the release of several glycoproteins from 3T6 mouse fibroblasts. These changes appear to relate to the influence of these compounds on the expression of the transformed phenotype of these cells.
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PMID:Retinoic acid and 12-O-tetradecanoylphorbol-13-acetate alter release of glycoproteins from mouse fibroblast BALB/C 3T6 cells. 391 54

Neoplastic transformation mediated by ras oncogenes is associated with deregulated expression of genes encoding, for example, various proteases, lysyl oxidase, and smooth-muscle alpha-actin. To define the role of these genes in the initiation or maintenance of the ras-transformed state, we compared their steady-state mRNA levels in two different sets of preneoplastic fibroblast lines, ras-transformed clones, and phenotypic revertants derived from them. Compared with the preneoplastic fibroblasts, the ras-transformed derivatives exhibited elevated levels of cathepsin L (major excreted protein), transin (stromelysin I, matrix metalloproteinase-3), and collagenase I (matrix metalloproteinase-1) mRNA but undetectable levels of lysyl oxidase mRNA. Partial restoration of lysyl oxidase transcription was observed in four of five phenotypic revertants derived from rat FE-8 and NIHpEJcl3 cells. The elevated levels of transin mRNA found in NIHpEJcl3 cells were diminished to the pretransformation level in interferon revertants but were not reduced in phenotypic rat FE-8 revertants expressing a high level of the ras oncoprotein. High steady-state levels of collagenase I mRNA were dependent on ras expression but were not closely associated with the transformed phenotype. High levels of cathepsin L mRNA were associated with neither high ras expression nor neoplastic transformation. The downregulation of smooth-muscle alpha-actin, characteristic of transformed cell lines, was not reversible in phenotypic revertants.
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PMID:Partial restoration of pre-transformation levels of lysyl oxidase and transin mRNAs in phenotypic ras revertants. 772 41

Gonadal steroidogenesis is regulated by pituitary gonadotropins and a locally produced, unidentified factor. A 70-kilodalton (kD) protein complex secreted from rat Sertoli cells was isolated. The complex, composed of 28- and 38-kD proteins, stimulated steroidogenesis by Leydig cells and ovarian granulosa cells in a dose-dependent and adenosine 3',5'-monophosphate-independent manner. The follicle-stimulating hormone-induced 28-kD protein appeared to be responsible for the bioactivity, but the 38-kD protein was indispensable for maximal activity. The 28- and 38-kD proteins were shown to be identical to the tissue inhibitor of metalloproteinase-1 (TIMP-1) and the proenzyme form of cathepsin L, respectively. Thus, a TIMP-1-procathepsin L complex is a potent activator of steroidogenesis and may regulate steroid concentrations and, thus, germ cell development in both males and females.
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PMID:Identification of a stimulator of steroid hormone synthesis isolated from testis. 777 58

Cathepsin L (CTSL) is a lysosomal cysteine protease with potent elastase and collagenase activities. Its high activity in the uterine lumen during the period of placental attachment has led to speculation that CTSL may play an important role during embryonic implantation in the pig. Cathepsins have also been implicated in blastocyst implantation in other species like cat, rat and man. We isolated a PAC clone containing the porcine CTSL gene and determined the complete DNA sequence of the gene, which spans about 5.6 kb and consists of eight exons. The CTSL transcript encodes a primary peptide of 334 amino acids sharing 73-78% identity with other mammalian cathepsin L precursor proteins. Based on fluorescence in situ hybridization and radiation hybrid mapping, the porcine CTSL gene was assigned to chromosome 10q11--> q12.
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PMID:Characterization and comparative mapping of the porcine CTSL gene indicates a novel synteny between HSA9q21-->q22 and SSC10q11-->q12. 1197 77