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Dive into the research topics where Masakazu Kamata is active.

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Featured researches published by Masakazu Kamata.


Proceedings of the National Academy of Sciences of the United States of America | 2007

Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates

Dong Sung An; Robert E. Donahue; Masakazu Kamata; Betty Poon; Mark E. Metzger; Si-Hua Mao; Aylin C. Bonifacino; Allen Krouse; Jean-Luc Darlix; David Baltimore; F. Xiao-Feng Qin; Irvin S. Y. Chen

RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1.


Nature | 2016

A shared neural ensemble links distinct contextual memories encoded close in time

Denise J. Cai; Daniel Aharoni; Tristan Shuman; Justin Shobe; Jeremy S. Biane; Weilin Song; Brandon Wei; Michael Veshkini; Mimi La-Vu; Jerry Lou; Sergio E. Flores; Isaac I. Kim; Yoshitake Sano; Miou Zhou; Karsten Baumgaertel; Ayal Lavi; Masakazu Kamata; Mark H. Tuszynski; Mark Mayford; Peyman Golshani; Alcino J. Silva

Recent studies suggest the hypothesis that a shared neural ensemble may link distinct memories encoded close in time1–13. According to the memory allocation hypothesis1,2, learning triggers a temporary increase in neuronal excitability14–16 that biases the representation of a subsequent memory to the neuronal ensemble encoding the first memory, such that recall of one memory increases the likelihood of recalling the other memory. Accordingly, we report that the overlap between the hippocampal CA1 ensembles activated by two distinct contexts acquired within a day is higher than when they are separated by a week. Multiple convergent findings indicate that this overlap of neuronal ensembles links two contextual memories. First, fear paired with one context is transferred to a neutral context when the two are acquired within a day but not across a week. Second, the first memory strengthens the second memory within a day but not across a week. Older mice, known to have lower CA1 excitability16,17, do not show the overlap between ensembles, the transfer of fear between contexts, or the strengthening of the second memory. Finally, in aged animals, increasing cellular excitability and activating a common ensemble of CA1 neurons during two distinct context exposures rescued the deficit in linking memories. Taken together, these findings demonstrate that contextual memories encoded close in time are linked by directing storage into overlapping ensembles. Alteration of these processes by aging could affect the temporal structure of memories, thus impairing efficient recall of related information.


Journal of Virology | 2007

Novel Nuclear Import of Vpr Promoted by Importin α Is Crucial for Human Immunodeficiency Virus Type 1 Replication in Macrophages

Yuko Nitahara-Kasahara; Masakazu Kamata; Takuya Yamamoto; Xianfeng Zhang; Yoichi Miyamoto; Koho Muneta; Sayuki Iijima; Yoshihiro Yoneda; Yasuko Tsunetsugu-Yokota; Yoko Aida

ABSTRACT Monocytes/macrophages are major targets of human immunodeficiency virus type 1 (HIV-1) infection. The viral preintegration complex (PIC) of HIV-1 enters the nuclei of monocyte-derived macrophages, but very little PIC migrates into the nuclei of immature monocytes. Vpr, one of the accessory gene products of HIV-1, is essential for the nuclear import of PIC in these cells, although the role of Vpr in the entry mechanism of PIC remains to be clarified. We have shown previously that Vpr is targeted to the nuclear envelope and then transported into the nucleus by importin α alone, in an importin β-independent manner. Here we demonstrate that the nuclear import of Vpr is strongly promoted by the addition of cytoplasmic extract from macrophages but not of that from monocytes and that the nuclear import activity is lost with immunodepletion of importin α from the cytoplasmic extract. Immunoblot analysis and real-time PCR demonstrate that immature monocytes express importin α at low levels, whereas the expression of three major importin α isoforms markedly increases upon their differentiation into macrophages, indicating that the expression of importin α is required for nuclear import of Vpr. Furthermore, interaction between importin α and the N-terminal α-helical domain of Vpr is indispensable, not only for the nuclear import of Vpr but also for HIV-1 replication in macrophages. This study suggests the possibility that the binding of Vpr to importin α, preceding a novel nuclear import process, is a potential target for therapeutic intervention.


Journal of Virology | 2000

Two putative alpha-helical domains of human immunodeficiency virus type 1 Vpr mediate nuclear localization by at least two mechanisms.

Masakazu Kamata; Yoko Aida

ABSTRACT To identify the domains of Vpr that are involved nuclear localization, we transfected HeLa cells with a panel of expression vectors that encode mutant Vpr protein with deletions or substitutions within putative domains. Immunofluorescence staining of transfected cells revealed that wild-type Vpr was localized predominantly in the nucleus and the nuclear envelope and certainly in the cytoplasm. Introduction of substitutions or deletions within αH1 or αH2 resulted, by contrast, in diffuse expression over the entire cell. In addition, double mutations within both of these α-helical domains led to the complete absence of Vpr from nuclei. Next, we prepared HeLa cells that express chimeric proteins which consist of the αH1 and αH2 domains fused individually with green fluorescent protein (GFP) and a Flag tag and extracted them with digitonin and Triton X-100 prior to fixation. Flag-αH1-GFP was detected in the nucleus but not in the cytoplasm, while Flag-αH2-GFP was retained predominantly in the nucleus and in a small amount in the cytoplasm. The immunostaining patterns were almost eliminated by substitutions in each chimeric protein. Thus, it appeared that the two α-helical domains might be involved in nuclear import by binding to certain cellular factors. Taken together, our data suggest that the two putative α-helical domains mediate the nuclear localization of Vpr by at least two mechanisms.


PLOS Pathogens | 2009

Reassessing the Role of APOBEC3G in Human Immunodeficiency Virus Type 1 Infection of Quiescent CD4+ T-Cells

Masakazu Kamata; Yoshiko Nagaoka; Irvin S. Y. Chen

HIV-1 is restricted for infection of primary quiescent T-cells. After viral entry, reverse transcription is initiated but is not completed. Various hypotheses have been proposed for this cellular restriction including insufficient nucleotide pools and cellular factors, but none have been confirmed as the primary mechanism for restriction. A recent study by Chiu et al. implicates APOBEC3G, an anti-retroviral cytidine deaminase, as the cellular restriction factor. Here, we attempted to confirm these findings using the same strategy as reported by Chiu et al. of siRNA targeting knock-down of APOBEC3G expression. In contrast to the published study, our results do not support a role for APOBEC3G in restriction of HIV-1 in quiescent CD4+ T-cells. In our study, we tested the same siRNA as reported by Chiu et al. as well as two additional siRNAs targeting APOBEC3G, one of which showed 2-fold greater knock-down of APOBEC3G mRNA. However, none of the three siRNAs tested had a discernable effect on enhancing infection by HIV-1 in quiescent CD4+ T-cells. Therefore, we conclude that the primary mechanism of HIV-1 restriction in quiescent CD4+ T-cells remains to be elucidated.


Journal of Gene Medicine | 2010

Inhibition of HIV-1 infection by a unique short hairpin RNA to chemokine receptor 5 delivered into macrophages through hematopoietic progenitor cell transduction

Min Liang; Masakazu Kamata; Kevin N. Chen; Nonia Pariente; Dong Sung An; Irvin S. Y. Chen

We recently expressed a potent and noncytotoxic short hairpin (sh)RNA directed against chemokine (c‐c motif) receptor 5 (CCR5) using lentiviral mediated transduction of CD34+ hematopoietic progenitor cells (HPCs) and demonstrated the stable reduction of CCR5 expression in T‐lymphocytes.


Journal of Virology | 2004

Increased Levels of Wee-1 Kinase in G2 Are Necessary for Vpr- and Gamma Irradiation-Induced G2 Arrest

Huidong Yuan; Masakazu Kamata; Yiming Xie; Irvin S. Y. Chen

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) Vpr induces cell cycle arrest at the G2/M transition and subsequently apoptosis. Here we examined the potential involvement of Wee-1 in Vpr-induced G2 arrest. Wee-1 is a cellular protein kinase that inhibits Cdc2 activity, thereby preventing cells from proceeding through mitosis. We previously showed that the levels of Wee-1 correlate with Vpr-mediated apoptosis. Here, we demonstrate that Vpr-induced G2 arrest correlated with delayed degradation of Wee-1 at G2/M. Experimental depletion of Wee-1 by a small interfering RNA directed to wee-1 mRNA alleviated Vpr-induced G2 arrest and allowed apparently normal progression through M into G1. Similar results were observed when cells were arrested at G2 following gamma irradiation. Thus, Wee-1 is integrally involved as a key cellular regulatory protein in the signal transduction pathway for HIV-1 Vpr-induced cell cycle arrest.


PLOS ONE | 2012

Engineering HIV-1-resistant T-cells from short-hairpin RNA-expressing hematopoietic stem/progenitor cells in humanized BLT mice.

Gene-Errol Ringpis; Saki Shimizu; Hubert Arokium; Joanna Camba-Colón; Maria V. Carroll; Ruth Cortado; Yiming Xie; Patrick Y. Kim; Anna Sahakyan; Emily L. Lowe; Munetoshi Narukawa; Fadi Kandarian; Bryan P. Burke; Geoff Symonds; Dong Sung An; Irvin S. Y. Chen; Masakazu Kamata

Down-regulation of the HIV-1 coreceptor CCR5 holds significant potential for long-term protection against HIV-1 in patients. Using the humanized bone marrow/liver/thymus (hu-BLT) mouse model which allows investigation of human hematopoietic stem/progenitor cell (HSPC) transplant and immune system reconstitution as well as HIV-1 infection, we previously demonstrated stable inhibition of CCR5 expression in systemic lymphoid tissues via transplantation of HSPCs genetically modified by lentiviral vector transduction to express short hairpin RNA (shRNA). However, CCR5 down-regulation will not be effective against existing CXCR4-tropic HIV-1 and emergence of resistant viral strains. As such, combination approaches targeting additional steps in the virus lifecycle are required. We screened a panel of previously published shRNAs targeting highly conserved regions and identified a potent shRNA targeting the R-region of the HIV-1 long terminal repeat (LTR). Here, we report that human CD4+ T-cells derived from transplanted HSPC engineered to co-express shRNAs targeting CCR5 and HIV-1 LTR are resistant to CCR5- and CXCR4- tropic HIV-1-mediated depletion in vivo. Transduction with the combination vector suppressed CXCR4- and CCR5- tropic viral replication in cell lines and peripheral blood mononuclear cells in vitro. No obvious cytotoxicity or interferon response was observed. Transplantation of combination vector-transduced HSPC into hu-BLT mice resulted in efficient engraftment and subsequent stable gene marking and CCR5 down-regulation in human CD4+ T-cells within peripheral blood and systemic lymphoid tissues, including gut-associated lymphoid tissue, a major site of robust viral replication, for over twelve weeks. CXCR4- and CCR5- tropic HIV-1 infection was effectively inhibited in hu-BLT mouse spleen-derived human CD4+ T-cells ex vivo. Furthermore, levels of gene-marked CD4+ T-cells in peripheral blood increased despite systemic infection with either CXCR4- or CCR5- tropic HIV-1 in vivo. These results demonstrate that transplantation of HSPCs engineered with our combination shRNA vector may be a potential therapy against HIV disease.


Molecular Therapy | 2015

HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells

Anjie Zhen; Masakazu Kamata; Valerie Rezek; Jonathan Rick; Bernard Levin; Saro Kasparian; Irvin S. Y. Chen; Otto O. Yang; Jerome A. Zack; Scott G. Kitchen

The human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) response is critical in controlling HIV infection. Since the immune response does not eliminate HIV, it would be beneficial to develop ways to enhance the HIV-specific CTL response to allow long-term viral suppression or clearance. Here, we report the use of a protective chimeric antigen receptor (CAR) in a hematopoietic stem/progenitor cell (HSPC)-based approach to engineer HIV immunity. We determined that CAR-modified HSPCs differentiate into functional T cells as well as natural killer (NK) cells in vivo in humanized mice and these cells are resistant to HIV infection and suppress HIV replication. These results strongly suggest that stem cell-based gene therapy with a CAR may be feasible and effective in treating chronic HIV infection and other morbidities.


Journal of Virology | 2000

A carboxy-terminally truncated form of the human immunodeficiency virus type 1 Vpr protein induces apoptosis via G(1) cell cycle arrest.

Masako Nishizawa; Masakazu Kamata; Ryoichi Katsumata; Yoko Aida

ABSTRACT Viral protein R (Vpr) of human immunodeficiency virus type 1 inhibits cell proliferation by arresting the cell cycle at the G2 phase and inducing to apoptosis after G2arrest. We have reported previously that C81, a carboxy-terminally truncated form of Vpr, interferes with cell proliferation via a novel pathway that is distinct from G2 arrest. However, the mechanism of this effect of C81 is unknown. We demonstrate here that C81 can induce apoptosis via G1 arrest of the cell cycle. Immunostaining for various markers of stages of the cell cycle and flow cytometry analysis of DNA content showed that most HeLa cells that had been transiently transfected with a C81 expression vector were arrested at the G1 phase and not at the G2 or S phase of the cell cycle. Staining for annexin V, which binds phosphatidylserine on the plasma membrane, as an early indicator of apoptosis and measurement of the activity of caspase-3, a signaling molecule in apoptotic pathways, indicated that C81 is a strong inducer of apoptosis. Expression of C81 induced the condensation, fragmentation, and clumping of chromatin that are typical of apoptosis. Furthermore, the kinetics of the C81-induced G1 arrest were closely correlated with changes in the number of annexin V-positive cells and the activity of caspase-3. Replacement of Ile or Leu residues by Pro at positions 60, 67, 74, and 81 within the leucine zipper-like domain of C81 revealed that Ile60, Leu67, and Ile74 play important roles both in the C81-induced G1 arrest and in apoptosis. Thus, it appears that C81 induces apoptosis through pathways that are identical to those utilized for G1 arrest of the cell cycle. It has been reported that Ile60, Leu67, and Ile74 also play an important role in the C81-induced suppression of growth. These results suggest that the suppression of growth induced by C81 result in apoptosis that is independent of G2 arrest of the cell cycle.

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Dong Sung An

University of California

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Min Liang

University of California

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Yiming Xie

University of California

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Hubert Arokium

University of California

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Saki Shimizu

University of California

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Sanggu Kim

University of California

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Shen Pang

University of California

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