Endostatin, a M-r 20,000 COOH-terminal fragment of collagen XVIII, is currently in preclinical development as a novel antiangiogenic agent.
Endostatin is a potent antiangiogenic protein. Karumanchi et al. (2001) showed that alkaline phosphatase-tagged
endostatin bound endothelial cells, revealing 2 binding affinities. Expression cloning identified the cell surface
proteoglycn glypican, specifically glypican-1 (OMIM 600395) or glypican-4 (OMIM 300168), as the lower-affinity receptor.
Biochemical and genetic studies indicated that the heparan sulfate glycosaminoglycans of glypican were critical for
endostatin binding. Furthermore, endostatin selected a specific octasulfated hexasaccharide from a sequence in heparin.
NCBI Summary:
This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. The proteolytically produced C-terminal fragment of type XVIII collagen is endostatin, a potent antiangiogenic protein. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Three transcripts have been identified for this gene.
General function
Hormone
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Cellular localization
Secreted
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Ovarian function
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Glycomic analyses of ovarian follicles during development and atresia. Hatzirodos N et al. To examine the detailed composition of glycosaminoglycans during bovine ovarian follicular development and atresia, the specialized stromal theca layers were separated from the stratified epithelial granulosa cells of healthy (n=6) and atretic (n=6) follicles in each of three size ranges: small (3-5mm), medium (6-9mm) and large (10mm or more) (n=29 animals). Fluorophore-assisted carbohydrate electrophoresis analyses (on a per cell basis) and immunohistochemistry (n=14) were undertaken. We identified the major disaccharides in thecal layers and the membrana granulosa as chondroitin sulfate-derived ?uronic acid with 4-sulfated N-acetylgalactosamine and ?uronic acid with 6-sulfated N-acetylgalactosamine and the heparan sulfate-derived ?uronic acid with N-acetlyglucosamine, with elevated levels in the thecal layers. Increasing follicle size and atresia was associated with increased levels of some disaccharides. We concluded that versican contains 4-sulfated N-acetylgalactosamine and it is the predominant 4-sulfated N-acetylgalactosamine proteoglycan in antral follicles. Another non- or 6-sulfated N-acetylgalactosamine proteoglycan(s), which is not decorin or an inter-a-trypsin inhibitor family member, is present in bovine antral follicles and associated with hitherto unknown groups of cells around some larger blood vessels. These areas stained positively for chondroitin/dermatan sulfate 6-sulfated N-acetylgalactosamine epitopes [antibodies 7D4, 3C5, 4C3 and 3B3(+)], similar to stem cell niches observed in other tissues. The sulfation pattern of heparan sulfate glycosaminoglycans appears uniform across follicles of different sizes and in healthy and atretic follicles. The heparan sulfate products detected in the follicles are likely to be associated with perlecan, collagen XVIII or betaglycan.
Expression regulated by
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Ovarian localization
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Hata K, et al reported the expression of the Endostatin gene in epithelial ovarian cancer.
The gene expression of this molecule in 23 normal ovaries with follicle or corpus
luteum and in 64 cases of epithelial ovarian cancer (27 serous, 18 mucinous,
13 endometrioid, 4 clear cell, and 2 undifferentiated carcinomas) was analyzed
by PCR of RNA after reverse transcription.
Endostatin gene expression in ovarian cancers (median, 0.14; range,
0.02-1.11) was significantly higher than that in normal ovaries with follicle
or corpus luteum (median, 0.08; range, 0.03-0.26; P = 0.009). International
Federation of Gynecology and Obstetrics stage (P = 0.009) and residual tumor
(P = 0.005) were significantly associated with endostatin gene expression;
however, other clinico pathological features (e.g., patient age at diagnosis,
histological subtype, and histological grade) were not significantly
associated with endostatin gene expression.