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Sequence analysis of East Asian cagA of Helicobacter pylori isolated from asymptomatic healthy Japanese and Thai individuals.

Hirai I, Yoshinaga A, Kimoto A, Sasaki T, Yamamoto Y

Current microbiology ( SPRINGER ) 62 ( 3 ) 855 - 60 2011年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

CagA, especially East Asian type, is one of the most important virulence factors of Helicobacter pylori, which is believed to contribute to the gastric cancer development. There is extreme sequence heterogeneity on 3' region of cagA gene, demonstrated by the sequence analysis of cagA of H. pylori strains isolated from gastric disease patients. However, whether such heterogeneity of the cagA gene sequence is related to the pathogenicity of H. pylori in the gastric cancer development is not certain. Therefore, in this study, the 3' region of cagA sequences isolated from asymptomatic healthy individuals in Japan and Thailand, which show high and low gastric cancer prevalence, respectively, were analyzed and compared with those from patients with gastric cancer. The CagA sequences analysis in 21 and 12 H. pylori DNA samples obtained from Japanese and Thai individuals, respectively, by the molecular phylogenetic method showed that the sequences were more conserved in the Thai individuals (concordance rates among Thai sequences, 93.9-100%) than in the Japanese individuals (concordance rates among Japanese sequences, 82.8-100%) as shown by unrooted neighbor-joining (N-J) consensus trees constructed with the sequence between Asn869 and Ala967 in CagA. CagA sequences in gastric cancer patients were obtained from published data; analysis of these sequences revealed that CagA sequences from almost all Thai individuals were concentrated in one branch. In contrast, CagA sequences from Japanese individuals were uniformly distributed throughout the N-J consensus tree. These results suggest that the difference in the CagA sequences between asymptomatic healthy Japanese and Thai individuals may be linked to the incidence of gastric cancer in Japan and Thailand.

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Molecular typing of Bartonella henselae DNA extracted from human clinical specimens and cat isolates in Japan.

Yanagihara M, Tsuneoka H, Hoshide S, Ishido E, Umeda A, Tsukahara M, Nojima J, Ichihara K, Hino K, Hirai I, Yamamoto Y

FEMS immunology and medical microbiology ( WILEY-BLACKWELL ) 60 ( 1 ) 44 - 8 2010年10月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Bartonella henselae is the causative agent of cat scratch disease (CSD). To clarify the population structure and relationship between human and cat strains of B. henselae, 55 specimens isolated in Japan, including 24 B. henselae DNA-positive clinical samples from CSD patients and 31 B. henselae isolates from domestic cats, were characterized by multilocus sequence typing (MLST) and the 16S-23S tRNA-Ala/tRNA-Ile intergenic spacer (S1) sequence, which were used previously for strain typing of B. henselae. Three different sequence types (STs) were identified by MLST, one of which was novel. Fifty-two strains (94.5%), including all strains detected in CSD patients, were assigned to ST-1. Eight S1 genotypes were observed, three of which were novel. The 52 ST-1 strains were classified into seven S1 genotypes, two of which were predominant in both human and cat strains. In addition, 5.5% of the strains (3/55) contained two different intergenic spacer S1 copies. These results indicate that the predominant B. henselae MLST ST-1 in Japan is a significantly genetically diverse population on the basis of the sequence diversity of intergenic spacer S1, and that highly prevalent S1 genotypes among cats are often involved in human infections.

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Laboratory surveillance for prospective plasmid-mediated AmpC beta-lactamases in the Kinki region of Japan.

Yamasaki K, Komatsu M, Abe N, Fukuda S, Miyamoto Y, Higuchi T, Ono T, Nishio H, Sueyoshi N, Kida K, Satoh K, Toyokawa M, Nishi I, Sakamoto M, Akagi M, Nakai I, Kofuku T, Orita T, Wada Y, Jikimoto T, Kinoshita S, Miyamoto K, Hirai I, Yamamoto Y

Journal of clinical microbiology ( AMER SOC MICROBIOLOGY ) 48 ( 9 ) 3267 - 73 2010年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Extended-spectrum beta-lactamases, plasmid-mediated AmpC beta-lactamases (PABLs), and plasmid-mediated metallo-beta-lactamases confer resistance to many beta-lactams. In Japan, although several reports exist on the prevalence of extended-spectrum beta-lactamases and metallo-beta-lactamases, the prevalence and characteristics of PABLs remain unknown. To investigate the production of PABLs, a total of 22,869 strains of 4 enterobacterial species, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis, were collected during six 6-month periods from 17 clinical laboratories in the Kinki region of Japan. PABLs were detected in 29 (0.13%) of 22,869 isolates by the 3-dimensional test, PCR analysis, and DNA sequencing analysis. PABL-positive isolates were detected among isolates from 13 laboratories. Seventeen of 13,995 (0.12%) E. coli isolates, 8 of 5,970 (0.13%) K. pneumoniae isolates, 3 of 1,722 (0.17%) K. oxytoca isolates, and 1 of 1,182 (0.08%) P. mirabilis isolates were positive for PABLs. Of these 29 PABL-positive strains, 20 (69.0%), 6 (20.7%), 2 (6.9%), and 1 (3.4%) carried the genes for CMY-2, DHA-1, CMY-8, and MOX-1 PABLs, respectively. Pattern analysis of randomly amplified polymorphic DNA and pulsed-field gel electrophoretic analysis revealed that the prevalence of CMY-2-producing E. coli strains was not due to epidemic strains and that 3 DHA-1-producing K. pneumoniae strains were identical, suggesting their clonal relatedness. In conclusion, the DHA-1 PABLs were predominantly present in K. pneumoniae strains, but CMY-2 PABLs were predominantly present in E. coli strains. The present findings will provide significant information to assist in preventing the emergence and further spread of PABL-producing bacteria.

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Characterisation of anti-Staphylococcus aureus activity of quercetin

Itaru Hirai, Mana Okuno, Reika Katsuma, Namie Arita, Masahiro Tachibana, Yoshimasa Yamamoto

INTERNATIONAL JOURNAL OF FOOD SCIENCE AND TECHNOLOGY ( WILEY-BLACKWELL ) 45 ( 6 ) 1250 - 1254 2010年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

P>Although many antibiotics are available for the treatment of bacterial infections, the emergence and global spread of antibiotic-resistant bacteria is a community-wide problem. To overcome this problem, we must explore alternative antimicrobials. This study investigated the antibacterial properties of quercetin, a flavonoid present in vegetables and fruits. Quercetin was tested against gram-positive and gram-negative bacteria and was found to exert selective antibacterial activity against Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), and Staphylococcus epidermidis. Some clinical MRSA strains showed remarkable susceptibility to quercetin. In combination with antibiotics, such as oxacillin, ampicillin, vancomycin, gentamicin, and erythromycin, quercetin showed markedly enhanced antibacterial activity against MRSA. We also report quercetin-induced aggregation of S. aureus cells; the morphological changes in these cells, as assessed by electron microscopy; and the colony-spreading ability of quercetin-sensitive MRSA, all of which revealed the unique antibacterial properties of quercetin against S. aureus.

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Chlamydia pneumoniae infection suppresses Staphylococcus enterotoxin B-induced proliferation associated with down-expression of CD25 in lymphocytes

Itaru Hirai, Maki Utsumi, Hiroyuki Yamaguchi, Yoshimasa Yamamoto

CANADIAN JOURNAL OF MICROBIOLOGY ( NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS ) 56 ( 4 ) 289 - 294 2010年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Chlamydia pneumoniae (Chlamydophila pneumoniae) infects lymphocytes and modulates their immune functions; this is critical in the development of chronic inflammatory diseases associated with this pathogen. Therefore, to clarify this immune modulation due to C. pneumoniae infection, the effect of this infection on the proliferation of human peripheral blood lymphocytes was examined. Lymphocytes were proliferated by stimulation with Staphylococcus aureus enterotoxin B, and the cell number was increased up to 3 times the unstimulated lymphocyte number. Further, induction of CD25 expression was observed in 55.8% of lymphocytes. Infection with C. pneumoniae suppressed the proliferation of almost half the lymphocytes induced by stimulation with S. aureus enterotoxin B, and CD25 induction was inhibited in 64.7% of lymphocytes. Inhibition of CD25 expression was observed in both infected and uninfected lymphocytes in culture. However, the expression of VLA4 was not affected by C. pneumoniae infection. Furthermore, inhibition was observed only by infection with viable C. pneumoniae and not by the heat-killed bacteria. These results suggest that C. pneumoniae affects lymphocyte function by inhibiting proliferation and CD25 expression in response to immunological stimulation, possibly via humoral mediator(s).

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High prevalence of CTX-M beta-lactamase-producing Enterobacteriaceae in stool specimens obtained from healthy individuals in Thailand.

Sasaki T, Hirai I, Niki M, Nakamura T, Komalamisra C, Maipanich W, Kusolsuk T, Sa-Nguankiat S, Pubampen S, Yamamoto Y

The Journal of antimicrobial chemotherapy ( OXFORD UNIV PRESS ) 65 ( 4 ) 666 - 8 2010年04月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

To determine the prevalence of CTX-M beta-lactamase-producing Enterobacteriaceae in stool specimens obtained from healthy individuals in a rural area of Thailand. Bacteria in stool specimens were screened for extended-spectrum beta-lactamase (ESBL) production on McConkey agar with cefotaxime and confirmed by the double-disc synergy test. Genetic detection and genotyping of CTX-M-type ESBL was performed by PCR with bacterial DNA extracted from isolates. A markedly high number (82 of 141, 58.2%) of the specimens showed the presence of CTX-M beta-lactamase-producing Enterobacteriaceae, as confirmed by both phenotypic and genetic examinations. The majority of the CTX-M beta-lactamase-producing bacteria were Escherichia coli (85.1%). The study revealed the wide dissemination of CTX-M beta-lactamase-producing Enterobacteriaceae in the healthy population.

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Infection of less virulent Helicobacter pylori strains in asymptomatic healthy individuals in Thailand as a potential contributing factor to the Asian enigma.

Hirai I, Sasaki T, Kimoto A, Yamamoto Y, Azuma T, Mahachai V, Hansomburana P, Lertkupinit C, Luangjaru S, Noophan P, Chanatrirattanapan R, Piyanirandr V, Sappajit T, Suthivarakom K, Sangsuk L, Wangroongsarb P

Microbes and infection ( ELSEVIER SCIENCE BV ) 12 ( 3 ) 227 - 30 2010年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

In Thailand, gastric cancer incidence is considerably low despite the high prevalence of Helicobacter pylori infection. We investigated the prevalence of H. pylori infection and the genotypes of cagA by using 179 stool specimens obtained from asymptomatic Thai individuals. In this study, the prevalence of H. pylori infection was 43.6%, and the detection rate of cagA-positive strains was 43.5%. In addition, the proportion of the highly virulent East-Asian type of cagA was 7.2%. These results indicate that the low prevalence of cagA-positive H. pylori strain as well as the low prevalence of East-Asian genotype cagA-positive strains may contribute to the low gastric cancer incidence. (C) 2009 Elsevier Masson SAS. All rights reserved.

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エクアドルおよびパナマ在住の健常人におけるHelicobacter pylori感染について―寄生虫共感染およびH.pylori病原因子の検討―

佐々木正大, 平井到, 山本容正

Clin Parasitol 20 ( 1 ) 105 - 107 2010年02月

掲載種別: 研究論文（学術雑誌）

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Establishment of shared antigen reactive cytotoxic T lymphocyte using co-stimulatory molecule introduced autologous cancer cells.

Hirohashi Y, Torigoe T, Hirai I, Tamura Y, Nakatsugawa M, Inoue Y, Kanaseki T, Kamiguchi K, Ikeda H, Sasaki A, Yamanaka N, Sato N

Experimental and molecular pathology ( ACADEMIC PRESS INC ELSEVIER SCIENCE ) 88 ( 1 ) 128 - 32 2010年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Cytotoxic T lymphocytes (CTLs) play an essential role in immunological responses for tumor rejection. In the past decade, many tumor-associated antigens (TAAs) have been identified predominantly in melanomas. Several clinical trials based on such antigenic peptides with or without adjuvants brought about partially favorable results, suggesting that identification of more immunogenic TAAs is needed. We show here the successful establishment of human leukocyte antigen (HLA)-A24-restricted CTL (TcLHK2 line1) from a pleural effusion of lung cancer patient, using B7.1 (CD80) transduced autologous lung cancer cells as an antigen-presenting cell (APC). TcLHK2 line1 recognized autologous lung adenocarcinoma cell line LHK2 in an HLA-A24-restricted fashion. Moreover, this CTL line also recognized allogeneic HLA-A24-positive lung adenocarcinoma cell line, gastric carcinoma cell line and melanoma cell line. These data raise the possibility that co-stimulatory molecule B7.1 (CD80) plays important role to overcome the immunological tolerance. Furthermore, TcLHK2 line1 is a useful tool for the identification of widely expressed shared antigens restricted by HLA-A24. Further analysis of this CTL and autologous cancer cell line will bring about novel TAAs. (C) 2009 Elsevier Inc. All rights reserved.

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Stability of Chlamydophila pneumoniae in a harsh environment without a requirement for acanthamoebae.

Matsuo J, Kobayashi M, Nakamura S, Mizutani Y, Yao T, Hirai I, Yamamoto Y, Yamaguchi H

Microbiology and immunology ( WILEY-BLACKWELL PUBLISHING, INC ) 54 ( 2 ) 63 - 73 2010年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

The effect of actual interactions between Chlamydophila pneumoniae and amoebae (Acanthamoeba) on the survival of C. pneumoniae was investigated. C. pneumoniae and amoebae were detected in 75 soil samples by IFU assay and PCR. Although C. pneumoniae could not be cultured, the DNA prevalence of C. pneumoniae and amoebae in natural soil was 20% and 92% (no correlation between the prevalence of DNA was observed). The viability of C. pneumoniae spiked in autoclaved soil was assessed by IFU assay and RT-PCR. Although the number of infective progeny decreased for three days, transcripts of C. pneumoniae were detected for up to 98 days independently of amoebae. The stability of C. pneumoniae in liquid medium was also assessed by IFU assay and transmission electron microscopy. The bacteria could survive at 15 degrees C for 14 days independently of amoebae. Bacteria cultured without amoebae were confirmed to have normal structures. Thus, the presence of amoebae has no effect on C. pneumoniae survival, and the bacteria can survive in the absence of host cells for an extended period of time.

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Assessment of East Asian-type cagA-positive Helicobacter pylori using stool specimens from asymptomatic healthy Japanese individuals.

Hirai I, Sasaki T, Kimoto A, Fujimoto S, Moriyama T, Yamamoto Y

Journal of medical microbiology ( SOC GENERAL MICROBIOLOGY ) 58 ( Pt 9 ) 1149 - 1153 2009年09月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Recent investigations have suggested that CagA, a virulence factor of Helicobacter pylori and known to have multiple genotypes, plays a critical role in the development of stomach cancer. However, the prevalence of cagA-positive H. pylori strains and the cagA genotypes have not been well studied in healthy individuals because of the difficulty in collecting gastric specimens. In the present study, we assessed the prevalence of infection with H. pylori, particularly the strains with the East Asian cagA genotype (which is more potent in causing gastric diseases), among healthy asymptomatic Japanese individuals by a noninvasive method using stool specimens. The H. pylori antigen was detected in 40.3 % of healthy asymptomatic adult individuals (n=186) enrolled in the study. For the detection and genotyping of the cagA gene, DNA was extracted from the stool specimens of these individuals and analysed by PCR. We detected the East Asian cagA genotype in the DNA samples of a significantly high number (63.1 %) of healthy asymptomatic Japanese individuals. These results indicate that a significant number of asymptomatic healthy Japanese individuals were infected with highly virulent H. pylori.

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Analysis of Helicobacter pylori Genotype in Stool Specimens of Asymptomatic People

Tadahiro Sasaki, Itaru Hirai, Ricardo Izurieta, Boo Hoe Kwa, Edmundo Estevez, Azael Saldana, Jose Calzada, Saori Fujimoto, Yoshimasa Yamamoto

LABMEDICINE ( AMER SOC CLINICAL PATHOLOGY ) 40 ( 7 ) 412 - 414 2009年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Background. Genotyping of Helicobacter pylori virulence factor is important in human health care. However, the genotyping of H. pylori infecting asymptomatic people is not well studied due to the difficulty in collecting gastric specimens. Methods: We analyzed 164 asymptomatic participants in Ecuador and Panama by utilizing stool specimens. H, pylori was detected using immunological methods. H. pylori virulence factor cagA was genotyped by PCR. Results: Helicobacter pylori antigen was found in 72.2% of participants from Ecuador and 54.1% from Panama. Among H. pylori DNA-positive samples, cagA was detected in 45.9% from Ecuador and 20.0% from Panama. Over 80% of the detected cagA from both countries was East-Asian genotype. Conclusions: The results suggest that our method is valuable for assessing the H. pylori infection status of asymptomatic people and that the prevalence of H. pylori infection and/or the occurrence of cagA in H. pylori may be related to the risk of stomach cancer.

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A method for assessment of Helicobacter pylori genotype using stool specimens.

Hirai I, Sasaki T, Fujimoto S, Moriyama T, Azuma T, Yamamoto Y

FEMS immunology and medical microbiology ( WILEY-BLACKWELL PUBLISHING, INC ) 56 ( 1 ) 63 - 6 2009年06月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Helicobacter pylori infection has been regarded as a major factor associated with the development of gastric diseases. The characterization of infected H. pylori in asymptomatic individuals is important for the prediction of the onset of such diseases. However, because of the difficulty in obtaining gastric biopsy samples, H. pylori in healthy subjects have not been studied sufficiently. Therefore, we tested a noninvasive method for the characterization of H. pylori using stool specimens. This method involved H. pylori antigen detection in stool specimens by immuno-chromatography; confirmation of H. pylori DNA by real-time PCR that involved the detection of its 16S rRNA gene in the DNA extracted from stool specimens; and nested PCR with genotype-specific primer pairs. A total of 80 samples obtained from asymptomatic subjects were assessed using this method. The results showed that the prevalence of H. pylori in asymptomatic Japanese individuals was 37.5%. The detection rate of the virulence factor gene cagA was 18.8%. Furthermore, all the detected cagA belonged to the highly virulent East-Asian type. These data suggest that the method used in this study is valuable for studying the molecular epidemiology of H. pylori infection in asymptomatic people.

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Immunosuppressive effect on T cell activation by interleukin-16- and interleukin-10-cDNA-double-transfected human squamous cell line.

Matsumoto Y, Fujita T, Hirai I, Sahara H, Torigoe T, Ezoe K, Saito T, Cruikshank WW, Yotsuyanagi T, Sato N

Burns : journal of the International Society for Burn Injuries ( ELSEVIER SCI LTD ) 35 ( 3 ) 383 - 9 2009年05月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

It is well known that induction of immunotolerance with allogeneic skin transplantation is generally difficult. This study attempted to find an immunosuppressive protocol for skin allograft rejection involving interleukin-16 (IL-16) and interleukin-10 (IL-10), because both are known to inhibit mixed lymphocyte reaction (MLR). The data indicated that IL-16 enhanced the immunosuppressive effect of IL-10. IL-16-cDNA- and IL-10-cDNA-double-transfected squamous cell carcinoma cell line were used as an in vitro model and they produced more than 20 ng/ml of IL-16 and 100 pg/ml of IL-10 in the supernatant, which significantly inhibited MLR and also the activation of allogeneic lymphocytes, which were stimulated directly by allogeneic double-cDNA-transfectant cells. Thus allogeneic skin graft producing IL-16 and IL-10 might have a local immunosuppressive action that could prolong graft survival. (c) 2008 Elsevier Ltd and ISBI. All rights reserved.

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[Analysis of Helicobacter pylori infection in a healthy Panamanian population].

Sasaki T, Hirai I, Yamamoto Y

Kansenshogaku zasshi. The Journal of the Japanese Association for Infectious Diseases 83 ( 2 ) 127 - 32 2009年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

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健常人保菌Helicobacter pyloriの検出と病原因子遺伝子解析

佐々木正大, 平井到, IZURIETA Richard, IZURIETA Richard, KWA Boo, 山本容正

臨床と微生物 35 ( 5 ) 475 - 480 2008年09月

掲載種別: 研究論文（学術雑誌）

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Disruption of the association of 73 kDa heat shock cognate protein with transporters associated with antigen processing (TAP) decreases TAP-dependent translocation of antigenic peptides into the endoplasmic reticulum.

Kamiguchi K, Torigoe T, Fujiwara O, Ohshima S, Hirohashi Y, Sahara H, Hirai I, Kohgo Y, Sato N

Microbiology and immunology ( BLACKWELL PUBLISHING ) 52 ( 2 ) 94 - 106 2008年02月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Major histocompatibility complex class I-bound antigenic peptides generated in the cytosol are translocated into the ER by TAP. In the present study, the physical association of HSC73 with TAP in human lymphoblastoid T I cells was demonstrated. The dissociation was induced in the presence of 10mM ATP, indicating that the ADP-binding form of HSC73 might be associated with TAP. We found that HSC73-binding immunosuppressant, MeDSG disrupted the HSC73-TAP association, whereas it did not affect the binding of HSC73 to a substrate protein. MHC class I expression on the cell surface was also downregulated. Then, the effect of MeDSG on the TAP-mediated ER translocation was examined using two homologous model peptides, NGT-Bw4 and NGT-Bw6, which had distinct binding affinity to HSC73. Although high-affinity peptide NGT-Bw4 was translocated by TAP, low-affinity peptide NGT-Bw6 was not. The TAP-dependent translocation of NGT-Bw4 was abolished in the presence of MeDSG. Decreased presentation on the cell surface was shown for the human leukocyte antigen (HLA) -A31-restricted natural antigenic peptide F4.2, which had high affinity to HSC73, in the presence of MeDSG. It was indicated that disruption of the HSC73-TAP association resulted in inhibition of TAP-dependent translocation of HSC73-bound peptides. Our findings highlighted an important role of HSC73 for feeding antigenic peptides to TAP, and suggested a possibility that a synthetic polyamine might inhibit the function of HSC73, thereby suppressing MHC class I-restricted presentation of HSC73-bound antigenic peptides.

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Loss of RPA1 induces Chk2 phosphorylation through a caffeine-sensitive pathway.

Araya R, Hirai I, Meyerkord CL, Wang HG

FEBS letters ( ELSEVIER SCIENCE BV ) 579 ( 1 ) 157 - 61 2005年01月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

RPA is an important component of DNA replication, repair and recombination, but its involvement in the signaling of cell-cycle checkpoints is not well understood. In this study, we show that knockdown of RPAI by siRNA duplexes induces ATM (Ser1981) and Chk2 (Thr68), but not Chk1 (Ser345) phosphorylation and results in p21 upregulation in HeLa cells. However, the induction of Chk2 (Thr68) phosphorylation and p21 expression by RPA1 siRNA transfection can be completely blocked by the ATM inhibitor caffeine. Moreover, transfection of siRNAs targeting ATM dramatically reduces Chk2 (Thr68) phosphorylation in RPA1 knockdown cells. Taken together, these results suggest that loss of RPA1 activates the Chk2 signaling pathway in an ATM-dependent manner. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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Human hRad1 but not hRad9 protects hHus1 from ubiquitin-proteasomal degradation.

Hirai I, Sasaki T, Wang HG

Oncogene ( NATURE PUBLISHING GROUP ) 23 ( 30 ) 5124 - 30 2004年07月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Three of the Rad family proteins, Rad9, Rad1, and Hus1, can interact with each other and form a heterotrimeric complex that is thought to play a role in the sensing step of the DNA integrity checkpoint pathways, but the nature of the Rad9 - Rad1 - Hus1 complex assembly remains enigmatic. Here, we demonstrate that the human hRad1 protein plays a significant role as molecular chaperone in the process of the hRad9 - hRad1 - hHus1 heterotrimeric complex formation. In contrast to hRad1, hHus1 is an unstable protein that is actively degraded via the ubiquitin - proteasome pathway. We show that treating cells with proteasome-specific inhibitors stabilizes hHus1 expression. Moreover, hRad1 can associate with hHus1 in the absence of hRad9 and protect hHus1 from ubiquitination and degradation in the cytoplasm. Importantly, genotoxic stress induces hRad1 expression and stabilizes the hHus1 protein. Taken together, these findings suggest a novel role of hRad1 as a potential intrinsic chaperone in the stabilization of hHus1 for the hRad9 - hRad1 - hHus1 checkpoint complex formation.

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Tumor-derived heat shock protein 70-pulsed dendritic cells elicit tumor-specific cytotoxic T lymphocytes (CTLs) and tumor immunity.

Ueda G, Tamura Y, Hirai I, Kamiguchi K, Ichimiya S, Torigoe T, Hiratsuka H, Sunakawa H, Sato N

Cancer science ( JAPANESE CANCER ASSOC ) 95 ( 3 ) 248 - 53 2004年03月 [ 査読有り ]

掲載種別: 研究論文（学術雑誌）

Vaccination with autologous tumor-derived heat shock proteins (Hsp), such as Hsp70, Hsp90 and gp96, has been demonstrated to elicit specific immune responses against the tumor from which the Hsps were isolated. The effect of Hsp immunization is wholly dependent on the presence of functional antigen-presenting cells (APCs) in the immunized host, and Hsp receptors on APCs have recently been identified. Here we show that bone marrow-derived dendritic cells (DCs) are able to internalize HSP-peptide complex and that peptides are re-presented by DCs via the major histocompatibility complex (MHC) class I presentation pathway. In addition, immunization with tumor-derived HSP-pulsed IDCs induces strong cytotoxic T cell (CTL) responses against multiple antigenic peptides in a transporter-associated antigen processing (TAP)-dependent manner. The results of the present study provide strong evidence of an efficient cross-priming activity of Hsp70, which could be exploited in the development of new and more effective immunotherapeutic strategies for cancer patients.

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