36 results on '"Akiyama, Tetsu"'
Search Results
2. PHOSPHATE exporter XPR1/SLC53A1 is required for the tumorigenicity of epithelial ovarian cancer.
- Author
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Akasu‐Nagayoshi, Yoko, Hayashi, Tomoatsu, Kawabata, Ayako, Shimizu, Naomi, Yamada, Ai, Yokota, Naoko, Nakato, Ryuichiro, Shirahige, Katsuhiko, Okamoto, Aikou, and Akiyama, Tetsu
- Abstract
Ovarian cancer is the fifth most common cause of cancer‐related death in women. Ovarian clear cell carcinoma (OCCC) is a chemotherapy‐resistant epithelial ovarian cancer with poor prognosis. As a basis for the development of therapeutic agents that could improve the prognosis of OCCC, we performed a screen for proteins critical for the tumorigenicity of OCCC using the CRISPR/Cas9 system. Here we show that knockdown of the phosphate exporter XPR1/SLC53A1 induces the growth arrest and apoptosis of OCCC cells in vitro. Moreover, we show that knockdown of XPR1/SLC53A1 inhibits the proliferation of OCCC cells xenografted into immunocompromised mice. These results suggest that XPR1/SLC53A1 plays a critical role in the tumorigenesis of OCCC cells. We speculate that XPR1/SLC53A1 might be a promising molecular target for the therapeutic treatment of OCCC. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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3. The splicing factor DHX38/PRP16 is required for ovarian clear cell carcinoma tumorigenesis, as revealed by a CRISPR‐Cas9 screen.
- Author
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Cona, Brandon, Hayashi, Tomoatsu, Yamada, Ai, Shimizu, Naomi, Yokota, Naoko, Nakato, Ryuichiro, Shirahige, Katsuhiko, and Akiyama, Tetsu
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CRISPRS ,NEOPLASTIC cell transformation ,RNA helicase ,GENOME editing ,CELL growth ,GENETIC variation - Abstract
Certain cancers, such as ovarian clear cell carcinoma (OCCC), display high levels of genetic variation between patients, making it difficult to develop effective therapies. In order to identify novel genes critical to OCCC growth, we carried out a comprehensive CRISPR‐Cas9 knockout screen against cell growth using an OCCC cell line and a normal ovarian surface epithelium cell line. We identified the gene encoding DHX38/PRP16, an ATP‐dependent RNA helicase involved in splicing, as critical for the growth and tumorigenesis of OCCC. DHX38/PRP16 knockdown in OCCC cells, but not normal cells, induces apoptosis and impairs OCCC tumorigenesis in a mouse model. Our results suggest that DHX38/PRP16 may play a role in OCCC tumorigenesis and could potentially be a promising therapeutic target. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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4. Higher incidence of zinc and nickel hypersensitivity in patients with irritable bowel syndrome.
- Author
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Kageyama, Yasunari, Aida, Koichi, Kawauchi, Kimihiko, Morimoto, Masafumi, Akiyama, Tetsu, and Nakamura, Tsutomu
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IRRITABLE colon ,ZINC ,NICKEL ,DENTAL metallurgy ,ALLERGIES ,INTESTINAL mucosa - Abstract
Introduction: The etiology of irritable bowel syndrome (IBS) remains elusive even though several genetic and environmental pathogenic factors have been reported. IBS is considered to be a functional disorder without any detectable lesions in the patient's bowel. However, many studies have demonstrated that a subset of IBS patients have low‐grade inflammation and aberrant T‐cell activation in their intestinal mucosa. To elucidate the immune mechanism underlying the mucosal inflammation in IBS, we focused on dental metal hypersensitivity, a T cell–mediated, delayed‐type allergic reaction that causes oral contact mucositis and systemic cutaneous inflammation. Methods: We recruited 147 Japanese IBS patients and 22 healthy controls (HCs). The subjects underwent the in vitro lymphocyte stimulation test to quantify their sensitivity to zinc, gold, nickel, and palladium, the metals that have been commonly used in dentistry. Results: A total of 56.5% of the IBS patients were hypersensitive to at least one metal species, whereas 31.8% of HC were hypersensitive to only a single metal species. The overall incidence of metal hypersensitivity was significantly higher for IBS patients than for HC. Furthermore, a significantly higher proportion of IBS patients were hypersensitive to zinc and/or nickel. The severity of the sensitivity to zinc and nickel was also significantly greater for IBS patients than for HC. There was no significant difference in the sensitization rates and the sensitivity among the IBS subtypes. Conclusions: This pilot study demonstrates that IBS patients have a significantly higher prevalence of hypersensitivity to zinc and nickel, suggesting the possible involvement of dental metal hypersensitivity in IBS pathogenesis in a subset of patients. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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5. Decreased Apoptosis and Persistence of the Common Nephric Duct During the Development of an Aberrant Vesicoureteral Junction in Dlg1 Gene-Targeted Mice.
- Author
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Iizuka‐Kogo, Akiko, Akiyama, Tetsu, and Senda, Takao
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- 2013
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6. Differences in the localization of the adenomatous polyposis coli- Asef/ Asef2 complex between adenomatous polyposis coli wild-type and mutant cells.
- Author
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Kawasaki, Yoshihiro, Furukawa, Shiori, Sato, Rina, and Akiyama, Tetsu
- Abstract
The tumor suppressor adenomatous polyposis coli ( APC) is mutated in familial adenomatous polyposis and in many sporadic colorectal tumors. Adenomatous polyposis coli is known to negatively regulate Wnt signaling by inducing the degradation of β-catenin. Adenomatous polyposis coli also interacts with the guanine nucleotide exchange factors Asef and Asef2 and stimulates their activity, thereby regulating cell adhesion and migration. Here we show that in confluent, non-motile MDCK II cells, Asef/ Asef2 are colocalized with APC at the sites of cell-cell adhesion at the apical and junctional levels. In contrast, in colorectal tumor cells containing mutated APC, significant amounts of Asef/ Asef2 and the truncated mutant APCs are localized mainly in the cytoplasm. These results suggest that localization of the Asef/ Asef2- APC complex at the sites of cell-cell contact is critical for the regulation of cell adhesion, and that the aberrant subcellular localization of these complexes in colorectal tumor cells may contribute to the cell's aberrant adhesive and migratory properties. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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7. Novel mouse model for Gardner syndrome generated by a large-scale N-ethyl- N-nitrosourea mutagenesis program.
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Toki, Hideaki, Inoue, Maki, Motegi, Hiromi, Minowa, Osamu, Kanda, Hiroaki, Yamamoto, Noriko, Ikeda, Ami, Karashima, Yuko, Matsui, Junko, Kaneda, Hideki, Miura, Ikuo, Suzuki, Tomohiro, Wakana, Shigeharu, Masuya, Hiroshi, Gondo, Yoichi, Shiroishi, Toshihiko, Akiyama, Tetsu, Yao, Ryoji, and Noda, Tetsuo
- Abstract
Mutant mouse models are indispensable tools for clarifying the functions of genes and elucidating the underlying pathogenic mechanisms of human diseases. We carried out large-scale mutagenesis using the chemical mutagen N-ethyl- N-nitrosourea. One specific aim of our mutagenesis project was to generate novel cancer models. We screened 7012 animals for dominant traits using a necropsy test and thereby established 17 mutant lines predisposed to cancer. Here, we report on a novel cancer model line that developed osteoma, trichogenic tumor, and breast cancer. Using fine mapping and genomic sequencing, we identified a point mutation in the adenomatous polyposis coli ( Apc) gene. The Apc1576 mutants bear a nonsense mutation at codon 1576 in the Apc gene. Although most Apc mutant mice established thus far have multifocal intestinal tumors, mice that are heterozygous for the Apc1576 mutation do not develop intestinal tumors; instead, they develop multifocal breast cancers and trichogenic tumors. Notably, the osteomas that develop in the Apc1576 mutant mice recapitulate the lesion observed in Gardner syndrome, a clinical variant of familial adenomatous polyposis. Our Apc1576 mutant mice will be valuable not only for understanding the function of the Apc gene in detail but also as models of human Gardner syndrome. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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8. A member of the ETS family, EHF, and the ATPase RUVBL1 inhibit p53-mediated apoptosis.
- Author
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Taniue, Kenzui, Oda, Takeaki, Hayashi, Tomoatsu, Okuno, Masumi, and Akiyama, Tetsu
- Abstract
Tumour cells are known to be dependent on, or 'addicted to', not only oncogenes, but also some non-oncogenes. However, the mechanisms by which tumour cells are addicted to these genes have not been fully explained. Here, we show that overexpression of a member of the ETS family, EHF, is required for the survival of colon tumour cells that contain wild-type p53. We found that EHF directly activates the transcription of RUVBL1, an ATPase associated with chromatin-remodelling complexes. RUVBL1 blocks p53-mediated apoptosis by repressing the expression of p53 and its target genes. Moreover, we found that RUVBL1 represses p53 transcription by binding to the p53 promoter, interfering with RNF20/hBRE1-mediated histone H2B monoubiquitination and promoting PAF1-mediated histone H3K9 trimethylation. These results indicate that EHF-mediated RUVBL1 expression allows colon tumour cells to avoid p53-mediated apoptosis. Thus, EHF and RUVBL1 might be promising molecular targets for the treatment of colon tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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9. The adenomatous polyposis coli-associated exchange factors Asef and Asef2 are required for adenoma formation in ApcMin/+mice.
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Kawasaki, Yoshihiro, Tsuji, Shinnosuke, Muroya, Ken, Furukawa, Shiori, Shibata, Yoko, Okuno, Masumi, Ohwada, Susumu, and Akiyama, Tetsu
- Abstract
Sporadic and familial colorectal tumours usually harbour biallelic adenomatous polyposis coli (APC)-associated mutations that result in constitutive activation of Wnt signalling. Furthermore, APC activates Asef and Asef2, which are guanine-nucleotide exchange factors specific for Rac1 and Cdc42. Here, we show that Asef and Asef2 expression is aberrantly enhanced in intestinal adenomas and tumours. We also show that deficiency of either Asef or Asef2 significantly reduces the number and size of adenomas in Apc
Min/+ mice, which are heterozygous for an APC mutation and spontaneously develop adenomas in the intestine. We observed that the APC–Asef/Asef2 complex induces c-Jun amino-terminal kinase-mediated transactivation of matrix metalloproteinase 9, and is required for the invasive activity of colorectal tumour cells. Furthermore, we show that Asef and Asef2 are required for tumour angiogenesis. These results suggest that Asef and Asef2 have a crucial role in intestinal adenoma formation and tumour progression, and might be promising molecular targets for the treatement of colorectal tumours. [ABSTRACT FROM AUTHOR]- Published
- 2009
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10. Ligand-dependent interaction between estrogen receptor α and adenomatous polyposis coli.
- Author
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Kouzmenko, Alexander P., Takeyama, Ken-ichi, Kawasaki, Yoshihiro, Akiyama, Tetsu, and Kato, Shigeaki
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ESTROGEN receptors ,TUMOR suppressor proteins ,COLON cancer ,CARCINOGENESIS ,ACETYLATION ,ESTROGEN - Abstract
Numerous independent clinical and experimental studies indicate that estrogens confer a protective effect against development of intestinal tumors, however the molecular mechanisms involved remain unclear. Physiological effects of estrogens are predominantly mediated by the action of nuclear estrogen receptors (ERs). A multifunctional protein adenomatous polyposis coli (APC) is a tumor suppressor and thought to act as a gatekeeper in colon tumorigenesis, as loss of function APC mutations trigger the development of colorectal cancer. Here we report that APC physically associates with ERa in the ligand-dependent manner. We have shown in the endogenous setting that the ligand-activated ERa recruits APC to the promoters in ER target genes and that increased levels of ER-dependent recruitment of APC enhances the ER transactivation through stimulation of histone acetylation. Found in majority of human colon tumors APC truncation mutants lost the ability to interact with ER. Thus, here we present the first evidence of a functional interaction between APC and ER that may be accounted for a tumor protective action of estrogens. [ABSTRACT FROM AUTHOR]
- Published
- 2008
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11. Human homolog of NOTUM, overexpressed in hepatocellular carcinoma, is regulated transcriptionally by β-catenin/TCF.
- Author
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Torisu, Yuichi, Watanabe, Akira, Nonaka, Aya, Midorikawa, Yutaka, Makuuchi, Masatoshi, Shimamura, Takahiro, Sugimura, Haruhiko, Niida, Atsushi, Akiyama, Tetsu, Iwanari, Hiroko, Kodama, Tatsuhiko, Zeniya, Mikio, and Aburatani, Hiroyuki
- Abstract
The Drosophila Notum gene, which is regulated by the Wingless pathway, encodes a secreted hydrolase that modifies heparan sulfate proteoglycans. In comparative analysis of the gene expression profiles in primary human hepatocellular carcinomas (HCC) and normal organs, we observed that the human ortholog of Drosophila Notum was overexpressed markedly in a subset of HCC, but expressed rarely in adult normal tissues. Immunoblotting confirmed the overexpression of NOTUM protein in 12 of 40 primary HCC cases (30%). High levels of NOTUM protein were significantly associated with intracellular (nuclear or cytoplasmic) accumulation of β-catenin protein: all 10 HCC with high intracellular β-catenin also had high NOTUM expression, whereas only 2 of 30 cases (6.7%) without intracellular β-catenin had high NOTUM expression ( P < 0.00001). NOTUM expression in HepG2 cells was downregulated significantly by induction of a dominant-negative mutant of TCF4, a β-catenin partner. In vivo binding of the β-catenin/TCF complex to the NOTUM promoter was demonstrated by chromatin immunoprecipitation in HepG2 and SW480 cells, where canonical Wnt signaling is activated constitutively. These findings provide evidence that NOTUM is a novel target of β-catenin/TCF4 and is upregulated in Wnt/β-catenin signaling-activated HCC. ( Cancer Sci 2008; 99: 1139–1146) [ABSTRACT FROM AUTHOR]
- Published
- 2008
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12. Novel clusters of highly expressed genes accompany genomic amplification in breast cancers
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Ito, Emi, Honma, Reiko, Yanagisawa, Yuka, Imai, Jun-ichi, Azuma, Sakura, Oyama, Tetsunari, Ohwada, Susumu, Akiyama, Tetsu, Nomura, Nobuo, Inoue, Jun-ichiro, Watanabe, Shinya, and Semba, Kentaro
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CANCER patients ,CHILDREN of cancer patients ,BREAST ,BREAST cancer - Abstract
Abstract: Breast cancer is the most common cancer in women worldwide. To identify novel amplicons involved in the mammary carcinogenesis, we constructed gene expression maps of chromosomes in 35 human breast cancer cell lines and extracted six candidate amplicons containing highly expressed gene clusters on chromosomes 8, 17, and X. We also confirmed the presence of the identified amplicons in clinical specimens by Southern blot analysis. Highly expressed genes identified in the amplicons will contribute to the characterization of breast cancer phenotypes, thereby providing novel targets for anticancer therapies. [Copyright &y& Elsevier]
- Published
- 2007
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13. Requirement of the tumour suppressor APC for the clustering of PSD-95 and AMPA receptors in hippocampal neurons.
- Author
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Shimomura, Atsushi, Ohkuma, Mahito, Iizuka‐Kogo, Akiko, Kohu, Kazuyoshi, Nomura, Ryuji, Miyachi, Ei‐ichi, Akiyama, Tetsu, and Senda, Takao
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TUMOR suppressor genes ,HIPPOCAMPUS (Brain) ,NEURONS ,FAMILIAL diseases ,SYNAPSES ,GENE expression - Abstract
Mutations in the adenomatous polyposis coli (APC) gene are associated with familial adenomatous polyposis and sporadic colorectal tumours. The APC gene is expressed ubiquitously in various tissues, especially throughout the large intestine and central nervous system (CNS). In the CNS, the expression of the APC protein is highest during embryonic and early postnatal development. APC associates through its C-terminal region with postsynaptic density (PSD)-95, a neuronal protein that participates in synapse development. Here, we examined the involvement of APC in synaptogenesis. In cultured hippocampal neurons, both overexpression of a dominant-negative construct that disrupts the APC–PSD-95 interaction and knockdown of APC expression using small interfering RNA (siRNA) inhibited the clustering of PSD-95 and a glutamate receptor subunit, and reduced alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA)-induced activity of AMPA receptors; however, the clustering of an N-methyl-d-aspartate (NMDA) receptor subunit was unaffected. These results are suggestive of APC involvement in the development of glutamatergic synapses. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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14. PX-RICS, a novel splicing variant of RICS, is a main isoform expressed during neural development.
- Author
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Hayashi, Tomoatsu, Okabe, Toshio, Nasu-Nishimura, Yukiko, Sakaue, Fumika, Ohwada, Susumu, Matsuura, Ken, Akiyama, Tetsu, and Nakamura, Tsutomu
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ENDOPLASMIC reticulum ,ORGANELLES ,ENDOSOMES ,PHOSPHOINOSITIDES ,AXONS ,DENDRITES - Abstract
In our previous study, we identified RICS, a novel β-catenin-interacting protein with the GAP activity toward Cdc42 and Rac1, and found that RICS plays an important role in the regulation of neural functions, including postsynaptic NMDA signaling and neurite outgrowth. Here we report the characterization of an N-terminal splicing variant of RICS, termed PX-RICS, which has additional phox homology (PX) and src homology 3 (SH3) domains in its N-terminal region. The PX domain of PX-RICS interacted specifically with phosphatidylinositol 3-phosphate [PtdIns(3)P], PtdIns(4)P and PtdIns(5)P. Consistent with this binding affinity, PX-RICS was found to be localized at the endoplasmic reticulum (ER), Golgi and endosomes. We also found that wild-type PX-RICS possessed much lower GAP activity than RICS, whereas a mutant form of PX-RICS whose PX domain lacks the binding ability to phosphoinositides (PIs) exhibited the GAP activity comparable to that of RICS. However, PX-RICS and RICS exhibited similar inhibitory effects on neurite elongation of Neuro-2a cells. Furthermore, we demonstrate that PX-RICS is a main isoform expressed during neural development. Our results suggest that PX-RICS is involved in early brain development including extension of axons and dendrites, and postnatal remodeling and fine-tuning of neural circuits. [ABSTRACT FROM AUTHOR]
- Published
- 2007
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15. Immunohistochemical expression of the β-catenin-interacting protein B9L is associated with histological high nuclear grade and immunohistochemical ErbB2/HER-2 expression in breast cancers.
- Author
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Toya, Hiroyuki, Oyama, Tetsunari, Ohwada, Susumu, Togo, Nozomi, Sakamoto, Ichiro, Horiguchi, Jun, Koibuchi, Yukio, Adachi, Shungo, Jigami, Takafumi, Nakajima, Takashi, and Akiyama, Tetsu
- Abstract
B9L/BCL9-2, a novel β-catenin-interacting protein, plays an important role in colorectal carcinogenesis by translocating β-catenin to the nucleus and enhancing β-catenin–T-cell factor-mediated transcription. To elucidate the role of B9L in breast cancers, we studied B9L expression in ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) of the breast immunohistochemically and compared it to the immunohistochemical expression of known proteins involved in breast carcinogenesis. In breast tissues, B9L immunoreactivity was present exclusively in the nuclei of normal and neoplastic ductal cells. In DCIS, immunohistochemical B9L expression was significantly associated with the tumor nuclear grade, comedo necrosis and the expression of ErbB2/HER-2, c-myc and p53. In IDC, B9L expression was correlated with ErbB2/HER-2 expression and tumor nuclear grade only. In both DCIS and IDC, immunohistochemical B9L expression was not related to the expression of cytoplasmic β-catenin. We demonstrated that nuclear B9L expression was closely associated with the high nuclear grade cancer phenotype and the expression of ErbB2/HER-2 in breast cancers. ( Cancer Sci 2007; 98: 484–490) [ABSTRACT FROM AUTHOR]
- Published
- 2007
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16. Up-regulation of a BCL9-related β-catenin-binding protein, B9L, in different stages of sporadic colorectal adenoma.
- Author
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Sakamoto, Ichiro, Ohwada, Susumu, Toya, Hiroyuki, Togo, Nozomi, Kashiwabara, Kenji, Oyama, Tetsunari, Nakajima, Takashi, Ito, Hideaki, Adachi, Shungo, Jigami, Takafumi, and Akiyama, Tetsu
- Abstract
Aberrant activation of Wnt signaling is a critical event in the development of human colorectal tumors. The aim of this study was to elucidate the role of B9L and its association with β-catenin in each stage of the adenoma-carcinoma sequence of human colorectal tumorigenesis. We investigated the expression levels of B9L in sporadic colorectal adenomas and carcinomas, categorized according to the Vienna classification, using real-time quantitative polymerase chain reaction (RTQ-PCR) and immunohistochemical analysis. B9L was expressed in the nuclei of non-neoplastic colonic mucosa cells and was overexpressed in the nuclei of neoplasias and invasive carcinoma cells. Immunoreactivity to B9L protein was correlated with the progressive grades of colorectal neoplasias, as was the expression of B9L mRNA. A high level of immunoreactivity to nuclear B9L was present in 27% of low-grade neoplasias and in more than 50% of high-grade neoplasias and invasive carcinomas, whereas a high level of nuclear B9L immunoreactivity was not observed in any of the non-neoplastic mucosa samples. The expression of B9L was dramatically increased in low-grade neoplasias compared with that in non-neoplastic mucosa. B9L may play an important role in tumorigenesis induced by aberrant activation of Wnt signaling and may act as a key protein in the progressive dysplasia of adenoma. ( Cancer Sci 2007; 98: 83–87) [ABSTRACT FROM AUTHOR]
- Published
- 2007
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17. Role of the Rho GTPase-activating protein RICS in neurite outgrowth.
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Nasu-Nishimura, Yukiko, Hayashi, Tomoatsu, Ohishi, Tomohiro, Okabe, Toshio, Ohwada, Susumu, Hasegawa, Yoshimi, Senda, Takao, Toyoshima, Chikashi, Nakamura, Tsutomu, and Akiyama, Tetsu
- Subjects
RHO GTPases ,G proteins ,NEURONS ,MICE ,CELLS - Abstract
The Rho family of small GTPases, including RhoA, Rac1 and Cdc42, are critical regulators of the actin cytoskeleton. In neuronal systems, Rho GTPase-activating proteins (RhoGAPs) and their substrates, Rho GTPases, have been implicated in regulating multiple processes in the morphological development of neurons, including axonal growth and guidance, dendritic elaboration and formation of synapses. RICS is mainly expressed in the brain and functions as a RhoGAP protein for Cdc42 and Rac1 in vitro. To examine the biological function of RICS, we disrupted the RICS gene in mice. RICS knockout mice developed normally and were fertile. However, when cultured in vitro, Cdc42 activity in RICS
–/– neurons was higher than that in wild-type neurons. Consistent with this finding, hippocampal and cerebellar granule neurons derived from RICS–/– mice bore longer neurites than those from wild-type mice. These findings suggest that RICS plays an important role in neurite extension by regulating Cdc42 in vivo. [ABSTRACT FROM AUTHOR]- Published
- 2006
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18. Human scribble, a novel tumor suppressor identified as a target of high-risk HPV E6 for ubiquitin-mediated degradation, interacts with adenomatous polyposis coli.
- Author
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Takizawa, Shin, Nagasaka, Kazunori, Nakagawa, Shunsuke, Yano, Tetsu, Nakagawa, Keiichi, Yasugi, Toshiharu, Takeuchi, Takamasa, Kanda, Tadahito, Huibregtse, Jon M., Akiyama, Tetsu, and Taketani, Yuji
- Subjects
PROTEINS ,DROSOPHILA ,TUMORS ,PAPILLOMAVIRUSES ,EPITHELIAL cells ,CELLS ,FRUIT flies - Abstract
Recently, we have identified human scribble (hScrib), human homolog of the Drosophila tumor suppressor Scribble, as a substrate of human papillomavirus E6 oncoproteins for ubiquitin-mediated degradation dependent on ubiquitin-protein ligase E6AP. Human Scribble, classified as a LAP protein containing eucine-rich repeats nd DZ domains, interacts with E6 through its PDZ domains and C-terminal PDZ domain-binding motif of E6 protein. Interaction between human Discs Large (hDlg), which is a substrate of E6 for the ubiquitin-mediated degradation, and adenomatous polyposis coli (APC) has been shown. Here, we investigated whether hScrib and APC interact with each other in vitro and in vivo. Interaction between hScrib and APC is mediated by the PDZ domains 1 and 4 of hScrib and C-terminal PDZ domain-binding motif of APC. Human Scribble co-localized with APC at the synaptic sites of hippocampal neuron and at the tip of membrane protrusion in the epithelial cell line. Interference of the interaction between hScrib and APC caused disruption of adherens junction. Knockdown of hScrib expression by RNAi disrupts localization of APC at the adherens junction. These data suggest that hScrib may participate in the hDlg-APC complex through its PDZ domains and regulate cell cycle and neural function by associating with APC. [ABSTRACT FROM AUTHOR]
- Published
- 2006
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19. Wnt signaling regulates the sequential onset of neurogenesis and gliogenesis via induction of BMPs.
- Author
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Kasai, Mana, Satoh, Kiyotoshi, and Akiyama, Tetsu
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DEVELOPMENTAL neurobiology ,NEUROGLIA ,BONE morphogenetic proteins ,RETROVIRUSES ,NEURONS ,ASTROCYTES - Abstract
In the mammalian central nervous system, neurogenesis precedes gliogenesis; neurons are primarily generated at the neural stage, whereas most glial cells are generated perinatally and postnatally. However, the signals that regulate this sequence of events remain unclear. Here we show that Wnt signaling induces neuronal and astroglial differentiation but suppresses oligodendroglial differentiation. We observed that precursor cells infected with a retrovirus encoding β-catenin differentiated into neurons, while astrocytes developed from uninfected precursor cells surrounding infected cells. As neurogenesis proceeded, expression of the bone morphogenetic proteins (BMPs), BMP2, 4 and 7, progressively increased in the cells infected with the retrovirus encoding β-catenin. Furthermore, treatment of cells with Noggin, a BMP antagonist, completely inhibited astroglial differentiation but partially restored oligodendroglial differentiation. These results suggest that Wnt signaling indirectly regulates gliogenesis by inducing BMPs in neuronal cells. Thus, cooperation between Wnt and BMP signaling may play a key role in determining the sequence of neurogenesis and gliogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2005
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20. Cloning of novel LERGU mRNAs in GPR30 3′ untranslated region and detection of 2 bp-deletion polymorphism in gastric cancer.
- Author
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Kakinuma, Naoto, Sato, Masaaki, Yamada, Tatsuya, Kohu, Kazuyoshi, Nakajima, Motowo, Akiyama, Tetsu, Ohwada, Susumu, and Shibanaka, Yasuhiko
- Subjects
MOLECULAR cloning ,MESSENGER RNA ,PROTEINS ,DNA ,THYMINE ,GASTROINTESTINAL cancer - Abstract
The improved IGCR (In–Gel Competitive Reassociation) method was applied to the analysis of human gastric cancer genomic DNA to identify its alterations, and it appeared that the IGCR library contained a fragment of 3′-untranslated region (3′ UTR) of G-protein coupled receptor 30 (GPR30) mRNA. When we searched genomic DNA pairs of gastric cancer patients with this IGCR clone, we found the deletion polymorphism with or without 2 bp (Cytosine and Thymine; CT). We confirmed the existence of a novel mRNA in GPR30 3′UTR by northern blotting, cloned this novel mRNA and named it Leucine Rich Protein in GPR30 3′UTR (LERGU). The EST database search gave one alternative splicing form in this 3′ UTR, which was named as LERGU-1. A novel alternative splicing form of this mRNA was also identified from the stomach total RNA, which was named LERGU-2. The LERGU mRNA was also detected in eight gastric cancer cell lines, but GPR30 mRNA scarcely existed. Furthermore, we detected the 2 bp-deletion form in genomic DNAs and mRNAs derived from gastric cancers, but not in other type cancers. Since the 2 bp-deletion position on LERGU corresponds to its alternative splicing site, this deletion may produce a frame-shifted protein. Overall, our findings suggest that a mutation or disappearance of the normal LERGU protein may have a function in the development of gastric cancer. (Cancer Sci2005; 96: 191–196) [ABSTRACT FROM AUTHOR]
- Published
- 2005
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21. MFB-1, an F-box-type ubiquitin ligase, regulates TGF-β signalling.
- Author
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Aoyama, Yukako, Urushiyama, Seiichi, Yamada, Misato, Kato, Chikako, Ide, Hiroko, Higuchi, Satoshi, Akiyama, Tetsu, and Shibuya, Hiroshi
- Subjects
TRANSFORMING growth factors ,UBIQUITIN ,LIGASES ,APOPTOSIS ,GENETICS ,TRANSGENES - Abstract
TGF-β signalling regulates cell growth, differentiation, morphogenesis and apoptosis. MAFbx/Atrogin-1 has been identified as a regulator for skeletal muscle atrophy and encodes an F-box-type E3 ubiquitin ligase. However, little is known about how MAFbx/Atrogin-1 regulates cellular signalling. Here, we identify and genetically characterize MFB-1, a MAFbx/Atrogin-1 homologue fromCaenorhabditis elegans. Themfb-1deletion mutant significantly enhanced the dauer constitutive (Daf-c) phenotype caused by mutations in the DAF-7/TGF-β-like signalling pathway, but not the DAF-2/insulin receptor-like signalling pathway. Conversely, the Daf-c phenotypes of DAF-7 pathway mutants were partially suppressed bymfb-1cDNA transgenes. Therefore, MFB-1 acts genetically downstream in the DAF-7 pathway. A mfb-1::GFP fusion was found to be expressed in the nervous system, hypodermis and intestine and overlapped expression of many DAF-7 pathway genes. We propose that MFB-1 is a novel F-box protein that negatively regulates dauer formation in concert with the DAF-7 signalling pathway inC. elegans. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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22. DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites.
- Author
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Moriguchi, Tetsuo, Haraguchi, Keiko, Ueda, Naoko, Okada, Masato, Furuya, Toshiom, and Akiyama, Tetsu
- Subjects
G proteins ,POLYMERASE chain reaction ,PROTEIN metabolism ,SCISSION (Chemistry) ,CELL adhesion molecules ,LIGANDS (Biochemistry) - Abstract
We have identified and characterized a novel member of the G protein-coupled receptor (GPCR) family, termed DREG. DREG belongs to the LNB-TM7 subfamily and possesses a long amino-terminus that contains a CUB domain, a PTX domain, a hormone binding domain and a GPCR proteolytic site (GPS) domain. RT-PCR experiments and whole mount in situ hybridization in mice showed that DREG is expressed at high levels in the heart and somite during embryogenesis and in the adult lung. When DREG was transiently expressed in mammalian cultured cells, a 35-kD fragment was generated by endogenous proteolytic processing at the conserved GPS domain. This short fragment was found associated with the cell membrane, typical of GPCRs. DREG was further cleaved in the middle of the extracellular domain, generating a soluble 70-kD fragment containing the CUB and PTX domains. This processing was inhibited by an inhibitor of the endoprotease furin but not of matrix metalloproteinases. These results raise the possibility that DREG plays a role in development, not only as a receptor or an adhesion molecule but also as a secreted ligand. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
23. The SH3, HOOK and guanylate kinase-like domains of hDLG are important for its cytoplasmic localization.
- Author
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Kohu, Kazuyoshi, Ogawa, Fumiaki, and Akiyama, Tetsu
- Subjects
TUMOR suppressor genes ,PHYSIOLOGICAL control systems - Abstract
Abstract Background: hDLG, the human homologue of the Drosophila tumour suppressor dlg , functions as a scaffolding protein that facilitates the transmission of diverse downstream signals. hDLG possesses multiple protein-binding domains, including three PDZ domains, an SH3 domain, a HOOK domain and a guanylate kinase-like (GK) domain. Results: We studied the significance of the PDZ, SH3, HOOK and GK domains in the cytoplasmic localization of hDLG. We found that mutation of the SH3 or GK domain, but not the PDZ domain, resulted in a re-localization of hDLG to the nucleus. Furthermore, hDLG was found to possess a potential nuclear localization signal in the HOOK domain. Conclusion: These results suggest that the SH3, HOOK and GK domains of hDLG are important for its cytoplasmic localization. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
24. SPAL, a Rap-specific GTPase activating protein, is present in the NMDA receptor-PSD-95 complex in the hippocampus.
- Author
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C. Roy, Badal, Kohu, Kazuyoshi, Matsuura, Ken, Yanai, Hiroyuki, and Akiyama, Tetsu
- Subjects
PROTEINS ,HIPPOCAMPUS (Brain) ,PROTEIN binding - Abstract
Abstract Background: The PSD-95 family of proteins possesses multiple protein binding domains, including three PDZ domains, an SH3 domain, a HOOK domain and a guanylate kinase-like (GK) domain. The PSD-95 proteins function as scaffolding proteins that link ion channels such as the N-methyl-d-aspartate-receptors (NMDA-Rs) with cytoskeletal networks and signalling molecules, thereby controlling synaptic plasticity and learning. Results: We found that the PSD-95 family proteins interact via their GK domains with SPA-1-like protein (SPAL), a GTPase-activating protein (GAP) that is specific for Rap1. SPAL was contained within the NMDA-R-PSD-95 complex, and co-localized with PSD-95 and NMDA-R at the synapses in cultured hippocampal neurones. Furthermore, NMDA stimulation induced the dephosphorylation of SPAL in cultured hippocampal neurones. Conclusion: Our findings suggest that SPAL may be involved in the NMDA-mediated organization of cytoskeletal networks and signal transduction. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
25. The hDLG-associated protein DAP interacts with dynein light chain and neuronal nitric oxide synthase.
- Author
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Haraguchi, Keiko, Satoh, Kiyotoshi, Yanai, Hiroyuki, Hamada, Fumihiko, Kawabuchi, Masahiro, and Akiyama, Tetsu
- Subjects
PROTEINS ,DYNEIN ,NITRIC-oxide synthases ,METHYL aspartate - Abstract
Postsynaptic density (PSD)-95 interacts with and mediates clustering of the N-methyl-d-aspartate-receptors (NMDA-R). PSD-95 also interacts with the hDLG-associated protein DAP, which is also called Synapse-associated protein 90-associated protein (SAPAP), and Guanylate kinase-associated protein (GKAP). DAP interacted directly with the dynein light chain (DLC) family of proteins. DLC was contained in the NMDA-R-PSD-95-DAP-neuronal nitric oxide synthase (nNOS) complex. Furthermore, DAP interacted with nNOS and recruited it into the Triton X-100-insoluble fraction of transfected cells. DAP interacts directly with DLC and nNOS, and links these proteins to the NMDA-R-PSD-95 complex. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
26. The colorectal tumour suppressor APC is present in the NMDA-receptor-PSD-95 complex in the brain.
- Author
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Yanai, Hiroyuki, Satoh, Kiyotoshi, Matsumine, Akihiko, and Akiyama, Tetsu
- Subjects
PROTEINS ,TUMOR suppressor genes ,METHYL aspartate - Abstract
Background The synaptic protein PSD-95/SAP90 interacts with ion channels such as the N-methyl-D-aspartate-receptor (NMDA-R) via its PDZ domain, and is involved in their clustering. Moreover, it interacts with signalling molecules and plays an important role in coupling NMDA-R to pathways that control synaptic plasticity and learning. Results We report that PSD-95 interacts with the adenomatous polyposis coli (APC) tumour suppressor protein via its PDZ domain. Furthermore, we found that PSD-95, NMDA-R and APC are contained in the same complex in vivo. PSD-95-NMDA-R–APC association was found to require two cysteine residues conserved in the amino-terminus of PSD-95 that are known to be critical for its multimerization. Conclusion Our findings suggest that the PSD-95-NMDA-R-APC complex forms due to the multimerization of PSD-95 monomers, each of which can associate with either NMDA-R or APC. It is possible that APC is involved in the regulation of ion channel clustering and/or organization of signalling molecules. [ABSTRACT FROM AUTHOR]
- Published
- 2000
- Full Text
- View/download PDF
27. Identification and characterization of E-APC, a novel Drosophila homologue of the tumour suppressor APC.
- Author
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Nishida, Ayumu, Fujita, Fumitaka, Tomoyasu, Yoshinori, Nakamura, Makoto, Toyoshima, Kumao, Tabata, Tetsuya, Ueno, Naoto, and Akiyama, Tetsu
- Subjects
GENETIC disorders ,DROSOPHILA - Abstract
Background Mutations in the adenomatous polyposis coli (APC) tumour suppressor gene are implicated in the genesis of colorectal cancers. The product of the APC gene forms a complex with β-catenin, glycogen synthase kinase 3β (GSK-3β) and Axin/conductin, and induces the degradation of β-catenin. Results We have identified a novel Drosophila homologue of APC, E-APC, which is similar to but differs in several respects from D-APC. The E-APC cDNA encodes a protein of predicted 1067 amino acids, with seven armadillo repeats, two copies of the 15-amino acid repeat, five copies of the 20-amino acid repeat, and one Axin/conductin binding site. E-APC directly interacts with D-Axin and Armadillo (Arm, the Drosophila homologue of β-catenin) in vitro, destabilizes intracellular β-catenin, and suppresses β-catenin/TCF-regulated transcription in APC
-/- colon cancer cells. The E-APC mRNA is ubiquitously expressed throughout all developmental stages in Drosophila. Conclusion Our findings suggest that E-APC may be universally involved in the regulation of the Wingless signalling pathway by down-regulating the level of Arm in Drosophila. [ABSTRACT FROM AUTHOR]- Published
- 1999
- Full Text
- View/download PDF
28. Axin, an inhibitor of the Wnt signalling pathway, interacts with β-catenin, GSK-3β and APC and reduces the β-catenin level.
- Author
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Nakamura, Tsutomu, Hamada, Fumihiko, Ishidate, Takao, Anai, Ken-ichi, Kawahara, Kohichi, Toyoshima, Kumao, and Akiyama, Tetsu
- Subjects
AMINO acids ,GENETIC transcription regulation ,PHYSIOLOGY - Abstract
Background:The Wnt/Wingless signalling pathway plays an important role in both embryonic development and tumorigenesis. β-Catenin and Axin are positive and negative effectors of the Wnt signalling pathway, respectively. Results:We found that Axin interacts with β-catenin and glycogen synthase kinase-3β (GSK-3β). Furthermore, the regulation of the G-protein signalling (RGS) domain of Axin is associated with the colorectal tumour suppressor adenomatous polyposis coli (APC). Overexpression of Axin in the human colorectal cancer cell line SW480 induced a drastic reduction in the level of β-catenin. Interaction with β-catenin and GSK-3β was required for the Axin-mediated β-catenin reduction. Conclusion:Axin interacts with β-catenin, GSK-3β and APC, and negatively regulates the Wnt signalling pathway, presumably by regulating the level of β-catenin. [ABSTRACT FROM AUTHOR]
- Published
- 1998
- Full Text
- View/download PDF
29. DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95.
- Author
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Satoh, Kiyotoshi, Yanai, Hiroyuki, Senda, Takao, Kohu, Kazuyoshi, Nakamura, Tsutomu, Okumura, Nobuaki, Matsumine, Akihiko, Kobayashi, Shigeru, Toyoshima, Kumao, and Akiyama, Tetsu
- Published
- 1997
- Full Text
- View/download PDF
30. An immunohistologic evaluation of C-erbB-2 gene product in patients with urinary bladder carcinoma.
- Author
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Sato, Kazunari, Moriyama, Masatsugu, Mori, Shigeo, Saito, Masahiro, Watanuki, Tsutomu, Terada, Kunihiko, Okuhara, Eiji, Akiyama, Tetsu, Toyoshima, Kumao, Yamamoto, Tadashi, Kato, Tetsuro, Sato, K, Moriyama, M, Mori, S, Saito, M, Watanuki, T, Terada, K, Okuhara, E, Akiyama, T, and Toyoshima, K
- Published
- 1992
- Full Text
- View/download PDF
31. Construction of Immunoradiometric Assay for Circulating c- erbB-2 Protooncogene Product in Advanced Breast Cancer Patients.
- Author
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Hosono, Makoto, Saga, Tsuneo, Sakahara, Harumi, Kobayashi, Hisataka, Shirato, Makoto, Endo, Keigo, Yamamoto, Tadashi, Akiyama, Tetsu, Toyoshima, Kumao, and Konishi, Junji
- Published
- 1993
- Full Text
- View/download PDF
32. In vitro and in vivo Release of Soluble erbB-2 Protein from Human Carcinoma Cells.
- Author
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Mori, Shigeo, Mori, Yasuyoshi, Mukaiyama, Taketo, Yamada, Yukinori, Sonobe, Yoshiko, Matsushita, Hirohisa, Sakamoto, Goi, Akiyama, Tetsu, Ogawa, Makoto, Shiraishi, Masato, Toyoshima, Kumao, and Yamamoto, Tadashi
- Published
- 1990
- Full Text
- View/download PDF
33. A Murine Monoclonal Antibody that Recognizes an Extracellular Domain of the Human c-erbB-2 Protooncogene Product.
- Author
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Masuko, Takashi, Sugahara, Kunio, Kozono, Mitsuko, Otsuki, Seiko, Akiyama, Tetsu, Yamamoto, Tadashi, Toyoshima, Kumao, and Hashimoto, Yoshiyuki
- Published
- 1989
- Full Text
- View/download PDF
34. Expression of the epidermal growth factor receptor in developing fetal mouse palates: An immunohistochemical study.
- Author
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Shiota, Kohei, Fujita, Shigeuki, Akiyama, Tetsu, and Mori, Chisato
- Published
- 1990
- Full Text
- View/download PDF
35. The novel lncRNA CALIC upregulates AXL to promote colon cancer metastasis.
- Author
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Kawasaki, Yoshihiro, Miyamoto, Masaya, Oda, Takeaki, Matsumura, Kosuke, Negishi, Lumi, Nakato, Ryuichiro, Suda, Sakiko, Yokota, Naoko, Shirahige, Katsuhiko, and Akiyama, Tetsu
- Abstract
Long non‐coding RNAs (lncRNAs) are aberrantly expressed in many disease conditions, including cancer. Accumulating evidence indicates that some lncRNAs may play critical roles in cancer progression and metastasis. Here, we identify a set of lncRNAs that are upregulated in metastatic subpopulations isolated from colon cancer HCT116 cells in vivo and show that one of these lncRNAs, which we name CALIC, is required for the metastatic activity of colon cancer cells. We show that CALIC associates with the RNA‐binding protein hnRNP‐L and imparts specificity to hnRNP‐L‐mediated gene expression. Furthermore, we demonstrate that the CALIC/hnRNP‐L complex upregulates the tyrosine kinase receptor AXL and that knockdown of CALIC or AXL using shRNA in colon cancer cells attenuates their ability to form metastases in mice. These results suggest that the CALIC/hnRNP‐L complex enhances the metastatic potential of colon cancer cells. Synopsis: The lncRNA CALIC associates with hnRNP‐L to induce AXL expression and to enhance the metastatic potential of colon cancer cells. The novel lncRNA CALIC is required for the metastatic activity of colon cancer cells.The novel lncRNA CALIC associates with the RNA‐binding protein hnRNP‐L to induce AXL expression.The CALIC/hnRNP‐L complex enhances the metastatic potential of colon cancer cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
36. SIRT2‐mediated inactivation of p73 is required for glioblastoma tumorigenicity.
- Author
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Funato, Kosuke, Hayashi, Tomoatsu, Echizen, Kanae, Negishi, Lumi, Shimizu, Naomi, Koyama‐Nasu, Ryo, Nasu‐Nishimura, Yukiko, Morishita, Yasuyuki, Tabar, Viviane, Todo, Tomoki, Ino, Yasushi, Mukasa, Akitake, Saito, Nobuhito, and Akiyama, Tetsu
- Abstract
Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells, including glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C‐terminal lysine residues. Our results suggest that SIRT2‐mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of glioblastoma. Synopsis: SIRT2 targets the tumor suppressor p73, thereby deacetylating its C‐terminus and suppressing its transcriptional activity. SIRT2‐mediated inactivation of p73 is crucial for the tumorigenicity of glioblastoma cells. The lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of glioblastoma cells.SIRT2 targets and regulates the transcriptional activity of the tumor suppressor p73.SIRT2‐mediated inactivation of p73 is critical for the proliferation and tumorigenicity of glioblastoma cells. SIRT2 targets the tumor suppressor p73, thereby deacetylating its C‐terminus and suppressing its transcriptional activity. SIRT2‐mediated inactivation of p73 is crucial for the tumorigenicity of glioblastoma cells. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
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