Defect in SHAP-Hyaluronan Complex Causes Severe Female Infertility

Zhuo, Lisheng; Yoneda, Masahiko; Zhao, Ming; Yingsung, Wannarat; Yoshida, Naoko; Kitagawa, Yasuo; Kawamura, Kazuo; Suzuki, Tamio; Kimata, Koji

doi:10.1074/jbc.c000899200

Cited by 251 publications

(256 citation statements)

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“…Thus far, numerous studies have shown involvement of ITIs in various pathological processes, including formation of urinary tract stones (Atmani and Khan, 1999;Janssen et al, 2001), female infertility (Zhuo et al, 2001), atherosclerosis and vascular disease (Onda et al, 1999;Fujita et al, 2004), and inflammation (Balduyck et al, 2000;Yingsung et al, 2003;Pineiro et al, 2004). Furthermore, several lines of evidence suggest a potential role of ITIs in tumour biology, particularly in the metastatic cascade and tumour progression (Kobayashi et al, 1995;Bourguignon et al, 1999;Paris et al, 2002;Zhang et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

et al. 2007

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Inter-a-trypsin inhibitors (ITIs) are protease inhibitors stabilizing the extracellular matrix. ITIs consist of one light (bikunin) and two heavy chains (ITIHs). We have recently characterized ITIH5, a novel member of the ITIH gene family, and showed that its messenger RNA is lost in a high proportion of breast tumours. In the present study, an ITIH5-specific polyclonal antibody was generated, validated with western blot and used for immunohistochemical analysis on a tissue microarray; ITIH5 was strongly expressed in epithelial cells of normal breast (n ¼ 11/15), while it was lost or strongly reduced in 42% (92/217) of invasive breast cancers. ITIH5 expression in invasive carcinomas was associated with positive expression of oestrogen receptor (P ¼ 0.008) and histological grade (P ¼ 0.024). Correlation of ITIH5 expression with clinical outcome revealed that patients with primary tumours retaining abundant ITIH5 expression had longer recurrence-free survival (RFS; P ¼ 0.037) and overall survival (OS; P ¼ 0.044), compared to those with reduced expression (mean RFS: 102 vs 78 months; mean OS: 120 vs 105 months). Methylation-specific PCR analysis frequently showed strong methylation of the ITIH5 promoter in primary breast tumours (41%, n ¼ 109) and breast cancer cell lines (n ¼ 6). Methylation was significantly associated with mRNA loss (Po0.001; n ¼ 39), and ITIH5 expression was induced after treatment of tumour cell lines with the demethylating agent 5-aza-2 0 -deoxycytidine. Moreover, ITIH5 promoter methylation was significantly associated with reduced OS (P ¼ 0.008). The cellular function of ITIH5 was evaluated by forced expression of a full-length ITIH5 complementary DNA in the breast cancer cell line MDA-MB-231, which does not endogenously express ITIH5. ITIH5-expressing clones showed a 40% reduced proliferation rate compared to mock-transfected cells. Overall, these data show that promoter methylation-mediated loss of ITIH5 expression is associated with unfavourable outcome in breast cancer patients, and thus ITIH5 could be used as a prognostic marker, although this marker is not multivariate independent due to its close association with ER expression. Our data indicate that ITIH5 is a candidate class II tumour suppressor gene and could be involved in tumour progression, invasion and metastasis, as its absence is associated with increased proliferation rates and a prognostic value indicating poor clinical outcome.

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Section: Discussionmentioning

confidence: 99%

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

et al. 2007

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“…In early studies on the matrices of cultured fibroblasts, mesothelial cells and cumulus-oocyte complexes (15,17), ITI and P␣I were shown to be able to stabilize the HA-rich matrices, suggesting a role for the SHAP-HA complex in stabilizing the HA-rich cell coats. Recently, SHAP-HA complex-deficient mice were generated, and the physiological importance of the complex established as being essential for the expansion of the cumulus oophorus (18). In preovulatory follicles, the cumulus cells start to synthesize HA actively upon a gonadotropin surge.…”

Section: Discussionmentioning

confidence: 99%

“…Hyperfilm ECL film and Sephacryl S-1000 were from Amersham Biosciences. Rabbit anti-human bikunin antibody (purified immunoglobulins) was prepared in this laboratory (18).…”

Section: Methodsmentioning

confidence: 99%

“…Recently, the in vivo implications of the SHAP-HA complex in the extracellular matrix have become evident from our study on bikunin-knockout mice that are unable to form the complex (18). In the mice, the cumulus oophorus, an investing structure unique to the oocyte of higher mammals, had a defect in forming the extracellular HA-rich matrix, and the ovulated oocyte was unfertilized, leading to severe female infertility (18). However, it is yet unclear how the SHAP-HA complex contributes to the stabilization of an HA-rich matrix.…”

mentioning

confidence: 98%

“…Previous studies (15,17) suggested that the ITI family molecules, ITI and P␣I, stabilized the HA-rich matrix of cultured cells and cumulus oophorus. Recently, the in vivo implications of the SHAP-HA complex in the extracellular matrix have become evident from our study on bikunin-knockout mice that are unable to form the complex (18). In the mice, the cumulus oophorus, an investing structure unique to the oocyte of higher mammals, had a defect in forming the extracellular HA-rich matrix, and the ovulated oocyte was unfertilized, leading to severe female infertility (18).…”

mentioning

confidence: 99%

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Molecular Heterogeneity of the SHAP-Hyaluronan Complex

Yingsung

Zhuo

Mörgelin

et al. 2003

Journal of Biological Chemistry

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We previously found that a covalent complex of SHAPs (serum-derived hyaluronan-associated proteins), the heavy chains of inter-␣-trypsin inhibitor family molecules, with hyaluronan (HA) is accumulated in synovial fluid of patients with rheumatoid arthritis, and the complex is circulated in patient plasma at high concentrations. How the SHAP-HA complex participates in this disease is unknown. To address this question, it is essential to clarify the structural features of this macromolecule. The SHAP-HA complex purified from synovial fluid of the patients by three sequential CsCl isopycnic centrifugations was heterogeneous in density, and the fractions with different densities had distinct SHAPto-HA ratios. Agarose gel electrophoresis and column chromatography revealed that there was no apparent difference in the size distribution of HA to which SHAPs were bound between the fractions with different densities. The SHAP-HA complex in the higher density fraction had fewer SHAP molecules per HA chain. Therefore, the difference between the fractions with different densities was due to a heterogeneous population of the SHAP-HA complex, namely the different number of SHAP molecules bound to an HA chain. Based on the SHAP and HA contents of the purified preparations, we estimated that an HA chain with a molecular weight of 2 ؋ 10 6 has as many as five covalently bound SHAPs, which could give a proteinaceous multivalency to HA. Furthermore, we also found that the SHAP-HA complex tends to form aggregates, judging from the migration and elution profiles in agarose gel electrophoresis and gel filtration, respectively. The multivalent feature of the SHAP-HA complex was also confirmed by the negative staining electron micrographic images of the purified fractions. Taken together, those structural characteristics may underlie the aggregate-forming and extracellular matrix-stabilizing ability of the SHAP-HA complex.

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DPAGT1‐Mediated Protein N‐Glycosylation Is Indispensable for Oocyte and Follicle Development in Mice

You

Tian

et al. 2020

Advanced Science

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Post‐translational modification of proteins by N ‐linked glycosylation is crucial for many life processes. However, the exact contribution of N ‐glycosylation to mammalian female reproduction remains largely undefined. Here, DPAGT1, the enzyme that catalyzes the first step of protein N ‐glycosylation, is identified to be indispensable for oocyte development in mice. Dpagt1 missense mutation (c. 497A>G; p. Asp166Gly) causes female subfertility without grossly affecting other functions. Mutant females ovulate fewer eggs owing to defective development of growing follicles. Mutant oocytes have a thin and fragile zona pellucida (ZP) due to the reduction in glycosylation of ZP proteins, and display poor developmental competence after fertilization in vitro. Moreover, completion of the first meiosis is accelerated in mutant oocytes, which is coincident with the elevation of aneuploidy. Mechanistically, transcriptomic analysis reveals the downregulation of a number of transcripts essential for oocyte meiotic progression and preimplantation development (e.g., Pttgt1 , Esco2 , Orc6 , and Npm2 ) in mutant oocytes, which could account for the defects observed. Furthermore, conditional knockout of Dpagt1 in oocytes recapitulates the phenotypes observed in Dpagt1 mutant females, and causes complete infertility. Taken together, these data indicate that protein N ‐glycosylation in oocytes is essential for female fertility in mammals by specific control of oocyte development.

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Defect in SHAP-Hyaluronan Complex Causes Severe Female Infertility

Cited by 251 publications

References 39 publications

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

The extracellular matrix protein ITIH5 is a novel prognostic marker in invasive node-negative breast cancer and its aberrant expression is caused by promoter hypermethylation

Molecular Heterogeneity of the SHAP-Hyaluronan Complex

DPAGT1‐Mediated Protein N‐Glycosylation Is Indispensable for Oocyte and Follicle Development in Mice

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