|Motoko Unoki||Last modified date：2021.10.23|
Associate Professor / Division of Epigenomics and Development
Department of Molecular and Structural Biology
Medical Institute of Bioregulation
Department of Molecular and Structural Biology
Medical Institute of Bioregulation
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Reseacher Profiling Tool Kyushu University Pure
Country of degree conferring institution (Overseas)
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Total Priod of education and research career in the foreign country
When I was an undergraduate student, I studied genetics of Carassius auratus langsdorfii (a Japanese crucian carp) which prospers by gynogenesis. Then I had studied carcinogenesis during my Ph.D course at the University of Tokyo, and continued the study at NCI in the US, and at RIKEN as a postdoc fellow for 11 years until I moved to Kyushu University as an assistant professor in 2010 (I was promoted to an associate professor in 2019). During the time, I identified UHRF1 as a novel methyl-CpG binding protein (Unoki et al., Oncogene, 2004). This finding contributed to open a door for clarifying molecular mechanism of maintenance DNA methylation by the DNMT1/UHRF1 complex. At Kyushu University, I discovered a novel histone modification “lysyl-hydroxylation” (Unoki et al., J. Biol. Chem., 2013), and also found that UHRF1 is partially involved in de novo DNA methylation during oocyte growth (Maenohara, Unoki et al., PLoS Genet., 2017). In 2015, I supported our Ph.D. student to identify CDCA7 and HELLS as causative genes for immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, which shows hypomethylation at centromer and pericentromere of chromosomes, by exome analysis (Thijssen et al., Nat. Commun., 2015). Currently, I’m trying to clarify functions of CDCA7 and HELLS. So far, I found that CDCA7 and HELLS are involved in non-homologous recombination (NHEJ) by facilitating access of Ku80 to DNA damage sites (Unoki et al., J. Clin., Invest., 2019). I also found that CDCA7 facilitates access of the DNMT1/UHRF1 complex to nascent DNA, and aberrant transcription from hypomethylated pericentromeric repeats in ICF patients causes R-loop formation, resulting in DNA damages (Unoki et al., Sci Rep., 2020). These findings are helpful for deepening the insights into mechanism of maintenance of DNA methylation and chromosome stability. In the future, I would like to contribute to care patients who suffer cancer and immunodeficiency by utilizing the knowledge which I have obtained.
Research InterestsMembership in Academic Society
- Analysis of protein-protein interactions involved in epigenetic regulation
keyword : UHRF1, epigenetics, histon modification, DNA methylation, ICF syndrome, cancer
|2.||Unoki M, DNA methylation mechanism
Chapter: Recent insights into the mechanisms of de novo and maintenance DNA methylation in mammals, INTECH, 10.5772/intechopen.89238, ISBN 978-1-83880-818-1, 2020.05, [URL].
|6.||Unoki M. et al., Bladder Cancer
Chapter: UHRF1 is a potential molecular marker for diagnosis and prognosis of bladder cancer, INTECH, DOI: 10.5772/26914, 2011.10, [URL].
|1.||Motoko Unoki, Chromatin remodeling in replication-uncoupled maintenance DNA methylation and chromosome stability：Insights from ICF syndrome studies, Genes to Cells, DOI: 10.1111/gtc.12850, 2021.06, [URL].|
|2.||Unoki M, Kumamoto K, Takenoshita S, Harris CC., Reviewing the current classification of inhibitor of growth family proteins., Cancer Sci., 2009.07, [URL].|
|3.||Unoki M, Kumamoto K, Harris CC., ING proteins as potential anticancer drug targets., Curr Drug Targets., 2009.05, [URL], Recent emerging evidence suggests that ING family proteins play roles in carcinogenesis both as oncogenes and tumor suppressor genes depending on the family members and on cell status. Previous results from non-physiologic overexpression experiments showed that all five family members induce apoptosis or cell cycle arrest, thus it had been thought until very recently that all of the family members function as tumor suppressor genes. Therefore restoration of ING family proteins in cancer cells has been proposed as a treatment for cancers. However, ING2 knockdown experiments showed unexpected results: ING2 knockdown led to senescence in normal human fibroblast cells and suppressed cancer cell growth. ING2 is also overexpressed in colorectal cancer, and promotes cancer cell invasion through an MMP13 dependent pathway. Additionally, it was reported that ING2 has two isoforms, ING2a and ING2b. Although expression of ING2a predominates compared with ING2b, both isoforms confer resistance against cell cycle arrest or apoptosis to cancer cells, thus knockdown of both isoforms is critical to remove this resistance. Taken together, these results suggest that ING2 can function as an oncogene in some specific types of cancer cells, indicating restoration of this gene in cancer cells could cause cancer progression. Because knockdown of ING2 suppresses cancer cell invasion and induces apoptosis or cell cycle arrest, ING2 may be an anticancer drug target. In this brief review, we discuss possible clinical applications of ING2 with the latest knowledge of molecular targeted therapies..|
|4.||Motoko Unoki, Current and potential anticancer drugs targeting members of the UHRF1 complex including epigenetic modifiers., Recent Pat Anticancer Drug Discov., 2011.01, [URL], Epigenetic modulators play significant roles in carcinogenesis. DNA methylation and histone modifications are the two major epigenetic modifications involved in transcriptional regulation. Many histone modification enzymes and DNMTs are up-regulated in cancer cells, and contribute to malignant transformation. The majority of the current "new generation" of anticancer drugs target abnormally overexpressed oncogenic proteins such as kinases or receptors which mediate oncogenic signal transmission. Overexpression or accumulation of these oncoproteins in cancer is caused directly or indirectly by genetic or epigenetic abnormalities in tumor-associated genes. Among these changes, epigenetic changes in DNA and histones can be caused by aberrant expression of epigenetic modulator proteins in cells. Recently, it has been revealed that UHRF1, which is up-regulated in various cancers, links DNA methylation and histone modifications through binding to hemi-methylated DNA, and also to trimethylated histone H3K9. The UHRF1 complex includes HDAC1, Tip60, G9a, and maintenance and de novo DNMTs. Many of these are reported to be involved in carcinogenesis. Several anticancer drugs targeting epigenetic-machinery such as HDAC inhibitors, and DNMT inhibitors have been developed. Even though these drugs showed some effect on several types of cancer, mild to severe adverse reactions have been observed. In this article, the relevant patents on the strategies to develop safer anticancer drugs targeting epigenetic modulators, focusing on members and modifiers of the UHRF1 complex, are discussed..|
|5.||Unoki M, Brunet J, Mousli M., Drug discovery targeting epigenetic codes: the great potential of UHRF1, which links DNA methylation and histone modifications, as a drug target in cancers and toxoplasmosis., Biochem Pharmacol., 2009.11, [URL], UHRF1 plays a central role in transferring methylation status from mother cells to daughter cells. Its SRA domain recognizes hemi-methylated DNA that appears in daughter DNA strands during duplication of DNA. UHRF1 recruits DNMT1 to the site and methylates both strands. UHRF1 also binds to HDAC1 and di- and tri-methyl K9 histone H3, ubiquitinates histone H3, and associates with heterochromatin formation, indicating that UHRF1 links histone modifications, DNA methylation, and chromatin structure. UHRF1 is a direct target of E2F1 and promotes G1/S transition. The tumor suppressor p53, which is deficient in 50% of cancers, down-regulates UHRF1 through up-regulation of p21/WAF1 and subsequent deactivation of E2F1. The expression levels of UHRF1 are up-regulated in many cancers, probably partially because of the absence of wild type p53, but it is probably regulated by several other factors. Knockdown of UHRF1 expression in cancer cells suppressed cell growth, suggesting that UHRF1 can be a useful anticancer drug target. Recently, it was revealed that UHRF1 plays important roles not only in carcinogenesis, but also in toxoplasmosis, which is occasionally fatal to people with a weakened immune system, and can cause blindness in the major pathology of ocular toxoplasmosis. Toxoplasma gondii, which causes toxoplasmosis, utilizes UHRF1 to control the cell cycle phase and enhance its proliferation. Thus, knockdown of UHRF1 can be effective at stopping the proliferation of the parasites in infected cells. In this review, we discuss several possible methods that can inhibit the multiple unique functions of UHRF1, which can be utilized for treating cancers and toxoplasmosis..|
|1.||Motoko Unoki, Jafar Sharif, Yuichiro Saito, Guillaume Velasco, Claire Francastel, Haruhiko Koseki, Hiroyuki Sasaki, CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats, Scientific Reports, doi.org/10.1038/s41598-020-74636-2, 10, 17865, 2020.09, [URL].|
|2.||Sharmin Aktar, Hiroyuki Sasaki, Motoko Unoki, Identification of ZBTB24 protein domains and motifs essential for heterochromatin localization and transcriptional activation, Genes to Cells, doi.org/10.1111/gtc.12723, 24, 11, 746-755, 2019.09, [URL].|
|3.||Motoko Unoki, Hironori Funabiki, Guillaume Velasco, Claire Francastel, Hiroyuki Sasaki, CDCA7 and HELLS mutations undermine non-homologous end joining in centromeric instability syndrome, J. Clin. Invest., doi: 10.1172/JCI99751, 129, 1, 78-92, 2019.01, [URL], Mutations in CDCA7 and HELLS that respectively encode a CXXC-type zinc finger protein and a SNF2 family chromatin remodeler cause immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome type 3 and 4, respectively. Here, we demonstrate that classical non-homologous end joining (C-NHEJ) proteins Ku80 and Ku70, as well as HELLS coimmunoprecipitated with CDCA7. The coimmunoprecipitation of the repair proteins was sensitive to nuclease treatment and an ICF3 mutation in CDCA7 that impairs its chromatin binding. The functional importance of these interactions was strongly suggested by the compromised C-NHEJ activity and significant delay in Ku80 accumulation at DNA damage sites in CDCA7 and HELLS deficient HEK293 cells. Consistent with the repair defect, these cells displayed increased apoptosis, abnormal chromosome segregation, aneuploidy, centrosome amplification, and significant accumulation of gH2AX signals. Although less prominent, cells mutated for the other ICF genes DNMT3B and ZBTB24 (responsible for ICF type 1 and 2, respectively) showed similar defects. Importantly, lymphoblastoid cells from ICF patients shared the same changes detected in the mutant HEK293 cells to varying degrees. Although the C-NHEJ defect alone did not cause CG hypomethylation, CDCA7 and HELLS are involved in maintaining CG methylation at centromeric and pericentromeric repeats. The defect in C-NHEJ may account for some common features of ICF cells, including centromeric instability, abnormal chromosome segregation, and apoptosis..|
|4.||Shoji Maenohara, Motoko Unoki, Hidehiro Toh, Hiroaki Ohishi, Jafar Sharif, Haruhiko Koseki, Hiroyuki Sasaki, Role of UHRF1 in De Novo DNA Methylation in Oocytes and Maintenance Methylation in Preimplantation Embryos, PLOS Genetics, 10.1371/journal.pgen.1007042. , 13, 10, e1007042, 2017.10, [URL], The methylation of cytosine at CG sites in the mammalian genome is dynamically reprogrammed during gametogenesis and preimplantation development. It was previously shown that oocyte-derived DNMT1 (a maintenance methyltransferase) is essential for maintaining and propagating CG methylation at imprinting control regions in preimplantation embryos. In mammalian somatic cells, hemimethylated-CG-binding protein UHRF1 plays a critical role in maintaining CG methylation by recruiting DNMT1 to hemimethylated CG sites. However, the role of UHRF1 in oogenesis and preimplantation development is unknown. In the present study, we show that UHRF1 is mainly, but not exclusively, localized in the cytoplasm of oocytes and preimplantation embryos. However, smaller amounts of UHRF1 existed in the nucleus, consistent with the expected role in DNA methylation. We then generated oocyte-specific Uhrf1 knockout (KO) mice and found that, although oogenesis was itself unaffected, a large proportion of the embryos derived from the KO oocytes died before reaching the blastocyst stage (a maternal effect). Whole genome bisulfite sequencing revealed that blastocysts derived from KO oocytes have a greatly reduced level of CG methylation, suggesting that maternal UHRF1 is essential for maintaining CG methylation, particularly at the imprinting control regions, in preimplantation embryos. Surprisingly, UHRF1 was also found to contribute to de novo CG and non-CG methylation during oocyte growth: in Uhrf1 KO oocytes, transcriptionally-inactive regions gained less methylation, while actively transcribed regions, including the imprinting control regions, were unaffected. We also found that de novo methylation was defective during the late stage of oocyte growth. To the best of our knowledge, this is the first study to demonstrate the role of UHRF1 in de novo DNA methylation in vivo. Our study reveals multiple functions of UHRF1 during the global epigenetic reprogramming of oocytes and early embryos..|
|5.||Motoko Unoki, Akiko Masuda, Naoshi Dohmae, Kyohei Arita, Masanori Yoshimatsu, Yukiko Iwai, Yoshinori Fukui, Koji Ueda, Ryuji Hamamoto, Masahiro Shirakawa, Hiroyuki Sasaki, Yusuke Nakamura, Lysyl 5-Hydroxylation, a Novel Histone Modification, by Jumonji Domain Containing 6 (JMJD6), J Biol Chem, 10.1074/jbc.M112.433284 , 288, 9, 6053-6062, 2013.03, [URL], JMJD6 is reported to hydroxylate lysyl residues of a splicing factor, U2AF65. In this study, we found that JMJD6 hydroxylates histone lysyl residues. In vitro experiments showed that JMJD6 has a binding affinity to histone proteins and hydroxylates multiple lysyl residues of histone H3 and H4 tails. Using JMJD6 knockout mouse embryos, we revealed that JMJD6 hydroxylates lysyl residues of histones H2A/H2B and H3/H4 in vivo by amino acid composition analysis. 5-hydroxylysine was detected at the highest level in histones purified from murine testis, which expressed JMJD6 at a significantly high level among various tissues examined, and JMJD6 overexpression increased the amount of 5-hydroxylysine in histones in human embryonic kidney 293 cells. These results indicate that histones are additional substrates of JMJD6 in vivo. Because 5-hydroxylation of lysyl residues inhibited N-acetylation and N-methylation by an acetyltransferase and a methyltransferase, respectively, in vitro, histone 5-hydroxylation may have important roles in epigenetic regulation of gene transcription or chromosomal rearrangement..|
|6.||Unoki M, Daigo D, Koinuma J, Tsuchiya E, Hamamoto R, Nakamura Y., UHRF1 is a novel diagnostic marker of lung cancer. , Br. J. Cancer, 10.1038/sj.bjc.6605717, 103, 2, 217-22, 2010.07, [URL], BACKGROUND: Lung cancer is the leading cause of cancer deaths worldwide. As the sensitivity and specificity of current diagnostic markers are not perfect, we examined whether ubiquitin-like with PHD and ring finger domains 1 (UHRF1), which is overexpressed in various cancers but not yet examined in lung cancer in large scale, can be a novel diagnostic marker of lung cancer.
METHODS: Immunohistochemical analysis using surgical specimens obtained from 56 US and 322 Japanese patients with lung cancer was performed.
RESULTS: The UHRF1 was stained specifically in the nuclei of cancer cells, but not in the other cells. The UHRF1 expression was observed in all histological types of lung cancer, especially in non-adenocarcinomas (non-ADCs), both in the US and Japanese cases. In 322 Japanese non-small cell lung cancer (NSCLC) cases, UHRF1 expression was associated with the histological type (higher in non-ADCs; P<0.00001), gender (higher in male; P=0.00082), smoking (higher in smokers; P=0.00004), pT factor (higher in advanced stage; P=0.00010), and pN factor (higher in cancers with metastasis in regional lymph nodes; P=0.00018). The UHRF1 expression was also associated with poor prognosis for NSCLC patients (P=0.0364). Although UHRF1 overexpression was associated with these malignant indicators, UHRF1 was detectable in half of lung cancer patients in an early pathological stage.
CONCLUSION: The UHRF1 is overexpressed in various types of lung cancer from early pathological stage. Therefore, detection of UHRF1 expression in tissue specimens by immunohistochemistry can be useful for diagnosis of lung cancer in all pathological stages..
|7.||Unoki M, Kelly JD, Neal DE, Ponder BAJ, Nakamura Y, Hamamoto R., UHRF1 is a novel molecular marker for diagnosis and the prognosis of bladder cancer., Br. J. Cancer, 10.1038/sj.bjc.6605123, 101, 1, 98-106, 2009.07, [URL], BACKGROUND: Bladder cancer is the second most common cancer of the urinary system. Early diagnosis of this tumour and estimation of risk of future progression after initial transuretherial resection have a significant impact on prognosis. Although there are several molecular markers for the diagnosis and prognosis for this tumour, their accuracy is not ideal. Previous reports have shown that UHRF1 (ubiquitin-like with PHD and ring-finger domains 1) is essential for cellular proliferation. In this study, we examined whether UHRF1 can be a novel molecular marker of bladder cancer.
METHODS: We performed real-time TaqMan quantitative reverse transcription-PCR and immunohistochemistry to examine expression levels of UHRF1 in bladder and kidney cancers.
RESULTS: Significant overexpression of UHRF1 was observed in bladder cancer. The overexpression was correlated with the stage and grade of the cancer. Although UHRF1 expression in muscle-invasive cancer was greater than in non-invasive (pTa) or superficially invasive (pT1) cancers, UHRF1 could still be detected by immunohistochemistry in these early-stage cancers. Overexpression of UHRF1 in bladder cancer was associated with increased risk of progression after transurethral resection. High expression of UHRF1 in kidney cancer was also observed. But the increased levels of UHRF1 in kidney cancer were less significant compared with those in bladder cancer.
CONCLUSION: Our result indicates that an immunohistochemistry-based UHRF1 detection in urine sediment or surgical specimens can be a sensitive and cancer-specific diagnostic and/or prognosis method, and may greatly improve the current diagnosis based on cytology..
|8.||Unoki M, Kumamoto K, Robles AI,Shen JC,Zheng ZM, Harris CC., A novel ING2 isoform, ING2b, synergizes with ING2a to prevent cell cycle arrest and apoptosis., FEBS Letters, 10.1016/j.febslet.2008.10.024, 582, 28, 3868-74, 2008.11, [URL], We identified a novel inhibitor of growth family member 2 (ING2) isoform, ING2b, which shares exon 2 with ING2a, but lacks the N-terminal p53 binding region. Contrary to ING2a, ING2b's promoter has no p53 binding sites. Consistently, activation of p53 led to suppression of ING2a, leaving ING2b unaffected. Through isoform-specific targeting, we showed that ING2a knockdown suppressed cell growth only in the presence of p53, ING2b knockdown had no effect on cell growth, and knockdown of both induced cell cycle arrest and apoptosis independently of p53. ING2a and ING2b have compensatory roles that protect cells from cell cycle arrest and apoptosis and may be involved in development of chemotherapeutic resistance..|
|9.||Unoki M, Bronner C, Mousli M., A concern regarding the current confusion with the human homolog of mouse Np95, ICBP90/UHRF1., Radiat Res., 10.1667/RR1209.1, 169, 2, 240-4, 2008.02, [URL], ICBP90/UHRF1, which is overexpressed in cancer cells and is down-regulated by p53, possesses a methylated CpG binding affinity and binds to the methylated promoters of tumor suppressor genes in cancer cells with HDAC1 and DNMT1, suggesting suppression of these genes and maintenance of methylation status which leads to carcinogenesis. Recently, it was reported that the human homolog of Np95 is different from ICBP90 but not from UHRF1. Because UHRF1 is the gene symbol of ICBP90, the claim is a little confusing; that is, UHRF1 and ICBP90 are identical. Because the previously published genomic structure of the ICBP90 gene needed to be revised and the registered ICBP90 sequence (AF129507) contains two rare polymorphisms or sequence errors, we think that confusion could occur. Here we show the revised ICBP90 gene structure and 366 polymorphisms in this gene. Our conclusion is that the human homolog of Np95 is ICBP90, whose gene symbol is UHRF1..|
|10.||Unoki M, Shen JC, Zheng ZM, Harris, CC., Novel splice variants of ING4 and their possible roles in regulation of cell growth and motility. , J Biol Chem., 10.1074/jbc.M606296200, 281, 45, 34677-86, 2006.11, [URL], The ING4 gene is a candidate tumor suppressor gene that functions in cell proliferation, contact inhibition, and angiogenesis. We identified three novel splice variants of ING4 with differing activities in controlling cell proliferation, cell spreading, and cell migration. ING4_v1 (the longest splice variant), originally identified as ING4, encodes an intact nuclear localization signal (NLS), whereas the other three splice variants (ING4_v2, ING4_v3, and ING4_v4) lack the full NLS, resulting in increased cytoplasmic localization of these proteins. We found that one of the three ING4 variants, ING4_v2, is expressed at the same level as the original ING4 (ING4_v1), suggesting that ING4 variants may have significant biological functions. Growth suppressive effects of the variants that have a partial NLS (ING4_v2 and ING4_v4) were attenuated by a weaker effect of the variants on p21(WAF1) promoter activation. ING4_v4 lost cell spreading and migration suppressive effects; on the other hand, ING4_v2 retained a cell migration suppressive effect but lost a cell spreading suppressive effect. Therefore, ING4_v2, which localized primarily into cytoplasm, might have an important role in the regulation of cell migration. We also found that ING4_v4 played dominant-negative roles in the induction of p21(WAF1) promoter activation and in the suppression of cell motility by ING4_v1. In addition, ING4 variants had different binding affinities to two cytoplasmic proteins, protein-tyrosine phosphatase, receptor type, f polypeptide (PTPRF), interacting protein (liprin), alpha1, and G3BP2a. Understanding the functions of the four splice variants may aid in defining their roles in human carcinogenesis..|
|11.||Unoki M, Nishidate T, Nakamura Y., ICBP90, an E2F-1 target, recruits HDAC1 and binds to methyl-CpG through its SRA domain., Oncogene, 10.1038/sj.onc.1208053, 23, 46, 7601-10., 2004.10, [URL], ICBP90, inverted CCAAT box-binding protein of 90 kDa, has been reported as a regulator of topoisomerase IIalpha expression. We present evidence here that ICBP90 binds to methyl-CpG when at least one symmetrically methylated-CpG dinucleotides is presented as its recognition sequence. A SET and RING finger-associated (SRA) domain accounts for the high binding affinity of ICBP90 for methyl-CpG dinucleotides. This protein constitutes a complex with HDAC1 also via its SRA domain, and bound to methylated promoter regions of various tumor suppressor genes, including p16INK4Aand p14ARF, in cancer cells. It has been reported that expression of ICBP90 was upregulated by E2F-1, and we confirmed that the upregulation was caused by binding of E2F-1 to the intron1 of ICBP90, which contains two E2F-1-binding motifs. Our data also revealed accumulation of ICBP90 in breast-cancer cells, where it might suppress expression of tumor suppressor genes through deacetylation of histones after recruitment of HDAC1. The data reported here suggest that ICBP90 is involved in cell proliferation by way of methylation-mediated regulation of certain genes..|
|12.||Unoki M, Nakamura Y., Methylation at CpG-islands in intron1 of EGR2 confers enhancer-like activity., FEBS Lett., 10.1016/S0014-5793(03)01092-5, 554, 1-2, 67-72, 2003.11, [URL], We previously demonstrated several lines of evidence indicating that early growth response 2 (EGR2) functions as a tumor suppressor, partly on the basis that its expression was often decreased in human tumors and cancer cell lines. Here we report a possible molecular mechanism to account for down-regulation of EGR2 in tumor cells. Although no genetic mutations in the gene or alterations in methylation status of its promoter were detected, we found a high degree of methylation at CpG islands in intron 1 of EGR2 in cell lines that were expressing this gene at a high level. Moreover, reporter gene experiments revealed that methylated intron 1 had somehow conferred enhancer-like activity. The data imply the existence of a previously unsuspected mechanism of gene expression regulation..|
|13.||Unoki M, Okutsu J, Nakamura Y. , Identification of a novel human gene, ZFP91, involved in acute myelogenous leukemia., Int J Oncol., 22, 6, 1217-23, 2003.06, [URL], To elucidate mechanisms leading to acute myelogenous leukemia (AML), to find sensitive markers and novel targets for drug therapy, and to allow choice of suitable chemotherapy for each affected individual, we previously compared expression of mRNA from mononuclear cells of AML patients with that of normal controls using a cDNA microarray. Data from that study identified many genes that were commonly up- or down-regulated in AML cells. Of these, we report here the identification of a novel gene whose expression was increased in 27 (93%) of the 29 AML cases whose PBMC preparations include >70% leukemia cells. The gene product, localized in nuclei, showed several characteristics of transcription factors: five zinc-finger domains, a leucine zipper, and several nuclear localization signals. Its 92.5% identity in amino-acid sequence to the murine penta zinc finger protein (mPZf; gene symbol Zfp91), led us to term it ZFP91. Anti-sense oligonucleotides inhibited expression of ZFP91, suppressed cell growth, and induced apoptosis. Our results suggest that ZFP91 is likely to play an important role in cell proliferation and/or anti-apoptosis, and may serve as a molecular marker for AML..|
|14.||Unoki M, Nakamura Y., EGR2 induces apoptosis in various cancer cell lines by direct transactivation of BNIP3L and BAK., Oncogene, 10.1038/sj.onc.1206222, 22, 14, 2172-85., 2003.04, [URL], EGR2 plays a key role in the PTEN-induced apoptotic pathway. Using adenovirus-mediated gene transfer to 39 cancer cell lines, we found that EGR2 could induce apoptosis in a large proportion of these lines by altering the permeability of mitochondrial membranes, releasing cytochrome c and activating caspase-3, -8, and -9. Analysis by cDNA microarray and subsequent functional studies revealed that EGR2 directly transactivates expression of BNIP3L and BAK. Our results helped to clarify the molecular mechanism of the apoptotic pathway induced by PTEN-EGR2, and suggested that EGR2 may be an excellent target molecule for gene therapy to treat a variety of cancers..|
|15.||Unoki M, Nakamura Y., Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway., Oncogene, doi:10.1038/sj.onc.1204608 , 20, 33, 4457-65, 2001.07, Defects in PTEN, a tumor suppressor, have been found in cancers arising in a variety of human tissues. To elucidate the tumor-suppressive function of this gene, we have been analysing expression profiles of cancer cells after introduction of exogenous PTEN. Those experiments identified 99 candidate genes that were transcriptionally transactivated. Among them, we report here the further analyses of eight genes, EGR2/Krox-20, BPOZ, APS, HCLS1/HS1, DUSP1/MKP1, NDRG1/Drg1/RTP, NFIL3/E4BP4, and a novel gene (PINK1, PTEN-induced putative kinase). Expression of six of them (PINK1, EGR2, HCLS1, DUSP1, BPOZ, and NFIL3) was decreased in ovarian tumors compared with corresponding normal tissues. Colony-formation assays using plasmid clones designed to express each gene indicated that EGR2 and BPOZ were able to suppress growth of cancer cells significantly; in particular, cancer-cell lines stably expressing BPOZ grew more slowly than control cells containing mock vector. Flow cytometry suggested that over-expression of BPOZ inhibited progression of the cell cycle at the G(1)/S transition. Anti-sense oligonucleotides for BPOZ or EGR2 effectively inhibited their expression, and cell growth was accelerated. Therefore both genes appear to be novel candidates as mediators of the PTEN growth-suppressive signaling pathway..|
|16.||Unoki M, Furuta S, Onouchi Y, Watanabe O, Doi S, Fujiwara H, Miyatake A, Fujita K, Tamari M, Nakamura Y., Association studies of 33 single nucleotide polymorphisms (SNPs) in 29 candidate genes for bronchial asthma: positive association a T924C polymorphism in the thromboxane A2 receptor gene., Hum Genet., 10.1007/s004390000267, 106, ４, 440-6, 2000.04, [URL], Although intensive studies have attempted to elucidate the genetic background of bronchial asthma (BA), one of the most common of the chronic inflammatory diseases in human populations, genetic factors associated with its pathogenesis are still not well understood. We surveyed 29 possible candidate genes for this disease for single nucleotide polymorphisms (SNPs), the most frequent type of genetic variation, in genomic DNAs from Japanese BA patients. We identified 33 SNPs, only four of which had been reported previously, among 14 of those genes. We also performed association studies using 585 BA patients and 343 normal controls for these SNPs. Of the 33 SNPs tested, 32 revealed no positive association with BA, but a T924C polymorphism in the thromboxane A2 receptor gene showed significant association (chi2=4.71, P=0.030), especially with respect to adult patients (chi2=6.20, P=0.013). Our results suggest that variants of the TBXA2R gene or some nearby gene(s) may play an important role in the pathogenesis of adult BA..|
|5.||Motoko Unoki, Jafar Sharif, Yuichiro Saito, Hiroyuki Sasaki, CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats, 第43回日本分子生物学会年会, 2020.12, [URL].|
|6.||Motoko Unoki, Hiroyuki Sasaki, CDCA7 and HELLS suppress DNA:RNA hybrid-associated DNA damage at pericentromeric repeats, 日本人類遺伝学会第65回大会, 2020.11, [URL].|
|8.||Motoko Unoki, Hironori Funabiki, and Hiroyuki Sasaki, Role of the CDCA7/HELLS chromatin remodeling complex in genome stability, 第42回日本分子生物学会, 2019.12, [URL].|
|9.||Motoko Unoki, Hironori Funabiki, Hiroyuki Sasaki, Relationship between the CDCA7/HELLS chromatin remodeling complex and NHEJ in molecular pathogenesis of ICF syndrome, 第14回生命医科学研究所ネットワーク国際シンポジウム, 2019.10.|
|10.||Motoko Unoki, Hironori Funabiki, Hiroyuki Sasaki, Relationship between the CDCA7/HELLS complex and NHEJ in molecular pathogenesis of ICF syndrome, 第13回日本エピジェネティクス研究会年会, 2019.05.|
|11.||Motoko Unoki, CDCA7 and HELLS mutations undermine non-homologous end joining in centromeric instability syndrome, 第２回 九州大学女性研究者ダイバーシティシンポジウム, 2019.03.|
|13.||Motoko Unoki, Hironori Funabiki, Hiroyuki Sasaki, ICF syndrome proteins CDCA7 and HELLS promote non-homologous end joining, 2018 Hot Spring Harbor symposium, 2018.10, [URL].|
|14.||Motoko Unoki, Hiroyuki Sasaki, ICF syndrome proteins CDCA7 and HELLS promote non-homologous end joining, 日本人類遺伝学会第63回大会, 2018.10, [URL].|
|15.||Motoko Unoki, Hironori Funabiki, Hiroyuki Sasaki, ICF syndrome proteins CDCA7 and HELLS promote non-homologous end joining, 2018 Cold Spring Harbor meeting: Epigenetics & Chromatin, 2018.09, [URL].|
|16.||Motoko Unoki, Hiroyuki Sasaki, CDCA7, which is defective in ICF syndrome, is involved in DNA damage repair, The 2018 Cold Spring Harbor Asia Conference, 2018.04, [URL].|
|17.||Motoko Unoki, Hiroyuki Sasaki, ICF syndrome genes CDCA7 and HELLS are essential for DNA damage repair, France-Japan Epigenetics Workshop 2017, 2017.11, [URL].|
|19.||Shoji Maenohara, Motoko Unoki, Hidehiro Toh, Hiroaki Ohishi, Jafar Sharif, Haruhiko Koseki, Hiroyuki Sasaki, Essential role of Uhrf1 during oocyte growth and preimplantation development, the 4th Cold Spring Harbor Asia conference on Chromatin, Epigenetics and Transcription, 2016.05, [URL].|
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- The genetics society of Japan
- The Japan Society of Human Genetics
- The molecular biology society of Japan
- The Japanese Society for Epigenetics
- American Association for Cancer Research
- Japanese Cancer Association