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( Naoyuki Taniguchi ),( Hiroaki Korekane ) 생화학분자생물학회(구 한국생화학분자생물학회) 2011 BMB Reports Vol.44 No.12
Branched N-glycans are produced by a series of glycosyltransferases including N-acetylglucosaminyltransferases and fucosyltransferases and their corresponding genes. Glycans on specific glycoproteins, which are attached via the action of glycosyltransferases, play key roles in cell adhesion and signaling. Examples of this are adhesion molecules or signaling molecules such as integrin and E-cadherin, as well as membrane receptors such as the EGF and TGF-β receptors. These molecules also play pivotal roles in the underlying mechanism of a variety of disease such as cancer metastasis, diabetes, and chronic obstructive pulmonary disease (COPD). Alterations in the structures of branched N-glycans are also hall marks and are useful for cancer biomarkers and therapeutics against cancer. This mini-review describes some of our recent studies on a functional glycomics approach to the study of branched N-glycans produced by N-acetylglucosaminyltransferases III, IV, V and IX (Vb) (GnT-III, GnT- IV, V and IX (Vb)) and fucosyltransferase 8 (Fut8) and their patho- physiological significance, with emphasis on the importance of a systems glycobiology approach as a future perspective for glycobiology. [BMB reports 2011; 44(12): 772-781]
Role of “glycan cycles” for understanding the role of glycans in disease biomarker and therperutics
Naoyuki Taniguchi 한국당과학회 2011 한국당과학회 학술대회 Vol.2011 No.1
The use of glycan changes in their structure and function play pivotal roles in novel biomarker discovery and disease therapeutics. For example, regarding cancer biomarkers, fucosylated AFP and fucosylated haptoglobin are promising cancer biomarkers for hepatocarcinoma and pancreatic cancer, respectively. Deletion of core fucose from IgG1 molecule results in 100 fold activation of ADCC (antibody dependent cellular cytotoxicity) activity in antibody therapy. We have recently proposed the concept of the “glycan cycle” as a functional unit of glycans that will permit the integration of glycan functions in relation to diseases For example, glucose enters the cell via a glucose transporter and is converted to UDP-GlcNAc via the hexosamine pathway. UDP-GlcNAc plays a key role in the cytosol and is then incorporated into the Golgi via the UDPGlcNAc transporter and serves as a donor substrate for various GlcNAc-transferases from GnT-I to GnT-VI. UDP-GlcNAc also serves as a donor for O-GlcNAc-transferase in the cytosol. These enzymes function to modify target proteins such as TGF-beta, the EGFR, and the glucose transporter. These receptors are localized on the cell surface and bind to lectins such as galectin-3. When the affinity of lectin binding is decreased due to changes in receptor glycosylation, the receptors are endocytosed and degraded in acidic endosome/lysosome, and the free monosaccharide is probably recycled. This conceptual “functional unit of the glycan cycle,” such as just described for GlcNAc, is intended to help developing the understanding of the integrative and dynamic analysis of glycan functions.
Shin Nishio,Satomi Aihara,Mototsugu Shimokawa,Akira Fujishita,Shuichi Taniguchi,Toru Hachisuga,Shintaro Yanazume,Hiroaki KOBAYASHI,Fumihiro Murakami,Fumitaka Numa,Kohei Kotera,Naofumi Okura,Naoyuki To 대한부인종양학회 2018 Journal of Gynecologic Oncology Vol.29 No.5
Objective: Palonosetron is effective for the management of acute and delayed chemotherapy-induced nausea and vomiting (CINV). While emetogenic carboplatin-based chemotherapy is widely used to treat gynecologic cancers, few studies have evaluated the antiemetic effectiveness of palonosetron in this setting. Methods: A multicenter, single-arm, open-label phase II trial was conducted to evaluate the safety and effectiveness of palonosetron in controlling CINV in patients with gynecologic cancer. Chemotherapy-naïve patients received intravenous palonosetron (0.75 mg/body) and dexamethasone before the infusion of carboplatin-based chemotherapy on day 1. Dexamethasone was administered (orally or intravenously) on days 2–3. The incidence and severity of CINV were evaluated using the patient-completed Multinational Association of Supportive Care in Cancer Antiemesis Tool and treatment diaries. The primary endpoint was the proportion of patients experiencing complete control (CC) of vomiting, with “no rescue antiemetic medication” and “no clinically significant nausea” or “only mild nausea” in the delayed phase (24–120 hours post-chemotherapy). Secondary endpoints were the proportion of patients with a complete response (CR: “no vomiting” and “no rescue antiemetic medication”) in the acute (0–24 hours), delayed (24–120 hours), and overall (0–120 hours) phases, and CC in the acute and overall phases. Results: Efficacy was assessable in 77 of 80 patients recruited. In the acute and delayed phases, the CR rates the primary endpoint, were 71.4% and 59.7% and the CC rates, the secondary endpoint, were 97.4% and 96.1%, respectively. Conclusion: While palonosetron effectively controls acute CINV, additional antiemetic management is warranted in the delayed phase after carboplatin-based chemotherapy in gynecologic cancer patients (Trial registry at UMIN Clinical Trials Registry, UMIN000012806).
Inhibition of heregulin signaling by N-glycan deleted soluble ErbB3
Motoko Takahashi,Yoshinao Wada,Michiko Tajiri,Motoko Araki,Yoshiki Yamaguchi,Naoyuki Taniguchi,YoshioKuroki 한국당과학회 2011 한국당과학회 학술대회 Vol.2011 No.1
ErbB signaling is implicated in the pathology of various types of carcinoma. Ligand binding to the extracellular domain of ErbB induces conformational changes that lead to homo- or heterodimerization of the receptors and subsequent signaling. It has been reported that N-glycans of the ErbB family regulate its function. We previously reported that N-glycans of EGFR are involved in receptor dimerization and endocytosis. N-glycans of ErbB3 are also involved in receptor dimerization and activation status; deletion of the N-glycan on Asn418 of ErbB3 leads to both spontaneous homodimerization of ErbB3 and heterodimerization of ErbB2-ErbB3. The promoted heterodimerization with ErbB2 leads to upregulation of receptor tyrosine phosphorylation, downstream signalings, and transforming activity. We recently found that N-glycans of ErbB4 also regulate ligand-induced signaling. Thus, N-glycans of the ErbB family seem to play an important role in receptor activation, especially in receptor dimerization. To examine the role of N-glycans of the ErbB in detail, we prepared a wild type and an N-glycan deleted mutant of sErbB3 (domains I, II, III and IV) and compared their properties. When added to culture cells expressing ErbB2 and ErbB3, the sErbB3 N418Q mutant downregulated the heregulin b signaling more effectively than the wild type sErbB3. Through mass spectrometry analysis, we were able to determine the structure of the N-glycan on Asn418 of sErbB3. This suggests that the specific N-glycan of sErbB3 regulates the binding status of sErbB3 to ligands or receptors. We consider that the sErbB3 N418Q mutant is a potent inhibitor of transforming activity of ErbB, and may have therapeutic applications in cancer.
Kim, Yong-Sam,Kang, Hye-Yeon,Kim, Jin-Young,Oh, Sejeong,Kim, Cheorl-Ho,Ryu, Chun Jeih,Miyoshi, Eiji,Taniguchi, Naoyuki,Ko, Jeong Heon WILEY-VCH 2006 Proteomics Vol. No.
<P>To gain a better understanding of the mechanism underlying colon cancer and to search for potential markers of colon cancer prognosis, a comparative proteomic analysis of colon cancer WiDr cells was conducted using 2-DE and lectin blot, followed by identification based on ESI-MS. Through these approaches 14 proteins were identified as candidate target proteins for N-acetylglucosaminyl transferase V (GnT-V) that would be expected to be implicated in the progression of colon cancer. We selected protein tyrosine phosphatase kappa (PTPκ) as a model protein to validate this approach to the discovery of novel biomarkers in colon cancer. PTPκ underwent an aberrant glycosylation in GnT-V-overexpressing WiDr cells, and the aberrantly glycosylated PTPκ was vulnerable to proteolytic cleavage. The enhanced cleavage of PTPκ in GnT-V-overexpressing cells was responsible for the mitigation of the homophilic binding capacity, resulting in an increase in cancer cell migration.</P>
Kim, Yong-Sam,Son, Ok Lye,Lee, Ju Yeon,Kim, Sun Hee,Oh, Sejeong,Lee, Yoon Suk,Kim, Cheorl-Ho,Yoo, Jong Shin,Lee, Jeong-Hwa,Miyoshi, Eiji,Taniguchi, Naoyuki,Hanash, Samir M.,Yoo, Hyang Sook,Ko, Jeong H WILEY-VCH Verlag 2008 Proteomics Vol.8 No.16
<P>N-acetylglucosaminyltransferase V (GnT-V) has been reported to be upregulated in malignant cancer cells, and its targets have been sought after with regard to biomarker identification. The low capacity and high false positive rates of 2-DE gel-based lectin blots using phytohemagglutinin-L<SUB>4</SUB> (L-PHA) prompted us to develop a novel protocol for identifying GnT-V targets, in which serum proteins were subjected to immunodepletion, alkylation, and lectin precipitation using L-PHA coupled to avidin–agarose bead complexes, and tryptic digestion. Proteins captured by L-PHA conjugates were analyzed by a nano-LC-FT-ICR/LTQ MS. Here, we report 26 candidate biomarkers for colorectal cancer (CRC) that show 100% specificity and sensitivities of greater than 50%. Not only can these candidate proteins be used as analytes for validation, but the novel protocol described herein can be applied to biomarker discovery in nonCRCs. </P>