Laboratories

Laboratory of Biomedical Sciences (Tokyo Metroporitan Institute of Medical Science) Recruiting students for the academic year 2018

Laboratory of Protein Metabolism

Professor Keiji TANAKA
Tokyo Metroporitan Institute of Medical Science
+81-3-5316-3337
E-mail: tanaka-kj{at}igakuken.or.jp
Lab HP

Introduction

【Key Words】Protein Degradation, Proteasome, Ubiquitin, Autophagy, Mitophagy

 Protein degradation plays an important role in the control of a diverse array of basic cellular activities by rapidly and unidirectionally catalyzing biological reactions. Over the past 25 years, we have focused on elucidating the structure and molecular/physiological functions of the proteasome that is a 2.5-MDa ATP-dependent multicatalytic protease complex. The proteasome, in collaboration with the ubiquitin (posttranslational modifier functioning as a proteolysis marker) system used for choice of target proteins, selectively degrades short-lived regulatory proteins as well as abnormal proteins that must be eliminated from the cells. Over the past decade, we have been aiming to elucidate assembling mechanisms, focusing on proteasome dedicated assembling chaperones,and molecular diversity of the proteasomes (i.e., discovery of the immunoproteasome and thymoproteasome). It is now clear that the ubiquitin/ proteasome system controls various biologically important processes, such as cell-cycle control, immune responses, metabolic regulation and developmental programs. Moreover, dysfunction of the proteasome system causes the incidences of intractable diseases, e.g. cancers, infectious diseases, and neurodegenerative diseases such as familial Parkinson’s disease. In our laboratory,four teams are studying to elucidate the molecular mechanism of the ubiquitinproteasome system.


Genome Dynamics Project

Professor Hisao MASAI
Tokyo Metroporitan Institute of Medical Science
+81-3-5316-3231
E-mail: masai-hs{at}igakuken.or.jp
Lab HP

Introduction

【Key Words】DNA replication, G-quadruplex, genome stability, cell cycle, chromatin architecture, DNA replication stress checkpoint, embryonic stem cells, cancer cells

 Precise duplication of genetic materials is central to the stable maintenance of genomes through generations. Defects in the genome copying processes would generate genomic instability which could ultimately result in various diseases including cancer. The goal of our studies is to understand the molecular basis of how the huge genomes are accurately replicated and the precise copies of the genetic materials are inherited to the next generation. Three billion base pairs of the human genome (2 meter long) are replicated with almost no errors during the 6-8 hr time span of the cell cycle. This requires an extreme level of coordination of temporal and spatial arrangements of chromatin organization and signaling events for initiation of DNA replication (Masai et al. Ann. Rev. Biochem. [2010]).
 We recently discovered novel and crucial roles of non-standard DNA structures in regulation of DNA replication and transcription. Notably, we found that G-quadruplex structures (Fig. 1), which are widely present on genomes (more than 370,000 on the human genome), regulate organization of chromatin architecture and initiation of DNA replication (Fig. 2; Kanoh et al. Nature Struct. Mol. Biol. [2015]). Our major goal is to establish a novel principle of the genome by elucidating the fundamental and universal functions of G-quadruplex and other non-B type DNA structures in regulation of various genome functions. Through these efforts, we will also explore the possibility that mutations found in various diseases including cancer are related to alteration of these non-B DNA structures, which are likely to be essential components of genomes but somehow have been disregarded in the past.
 Our other major projects include 1) Maintenance of genome integrity and its failure as a cause of diseases: Molecular dissection of cellular responses to replication stress, a major trigger for oncogenesis, and elucidation of mechanisms by which stalled forks are processed and the genome is protected from various insults, and of how the failure of this process leads to diseases and senescence (genetics and cell biology; Yang et al. Nature Commun. [2016], Matsumoto et al. Mol. Cell. Biol. [2017]), 2) Chromosome dynamics that determines cell fate and regulates cell proliferation: Elucidation of mechanisms regulating temporal and spatial regulation of genome duplication as well as coordination of replication, repair, recombination and transcription (genomics and molecular genetics; Hayano et al. Genes Dev. [2012]; Yamazaki et al. EMBO J. [2012] and Trends in Genetics [2013]), 3) Unraveling the universal mechanisms of origin firing and its regulation (molecular biology and enzymology), 4) DNA replication and development: Understanding the roles of replication factors or replication timing regulation during development/ differentiation processes or during the functioning of various tissues and organs (mice engineering), and 5) Application of the mechanisms of DNA replication in development of novel cancer treatment strategies targeting replication/checkpoint factors and new technologies for manipulation of cellular functions (drug discovery and cell engineering).
 To achieve these goals, we are using E.coli, fission yeast, various mammalian cell lines, embryonic stem cells and model animals. We would like ultimately to apply the basic knowledge on the mechanisms of stable genome maintenance to the diagnosis and therapy of the relevant diseases including cancer.
 We are recruiting highly motivated and interested individuals who are communicative and can share excitement with us in the laboratory. We have had students from many foreign countries including Korea, Malaysia, Taiwan, China, Canada, Italy, France and Germany and have been excited to have many different cultures in our laboratory. Please feel free to contact us at any time through e-mail or by telephone.


Fig. 1 G-quadruplex structures

Fig. 2 Rif1 regulates chromatin architecture near nuclear periphery by binding to G4 structures on the chromosome.


Schizophrenia Research Project

Professor Masanori ITOKAWA
Tokyo Metroporitan Institute of Medical Science
+81-3-5316-3228
E-mail:Itokawa-ms{at}igakuken.or.jp
Lab HP

Introduction

【Key Words】mental illness, mind, brain, molecular biology, genome

 Why is homo sapience suffered from mental illnesses? Numerous numbers of people in field of religion or philosophy had ever investigated the maze far past. Only three hundred years have passed since medical sciences involved in this theme. We are challenging to resolve the twister interwoven with brain and mind by using methods and tools of biology.
Functional psychiatric disease is the brain disorder causing emotional and thinking difficulty without any abnormal sings in electric encephalography or brain imaging. Schizophrenia is the major one of those as well as mood disorder
We perform genomic and metabolome analysis using blood samples from patients with schizophrenia in order to reveal pathophysiology of the disease. We create animal and culture cell-based model utilizing genetic polymorphisms and aberrant metabolism seen in the patients.
Human iPS cells induced from a schizophrenic patient carrying the rare genetic variation were differentiated to neural cells to be analyzed for investigation of pathophysiology of the disease.
Schizophrenia is a common disease that the prevalence is around 1% of population at any region of the world. Why has schizophrenia survived natural selection during human evolution? We are also seeking answer of the question by using our models of animals and culture cells.
Ego-function such as self-identity is also disturbed in patients with schizophrenia. We challenge to reveal ego and self-consciousness, the fields that had ever been investigated by religion or philosophy far past,by using tools and methods of molecular biology. Oxidative stress is a central mediator of advanced glycation end product (AGE) formation, and pyridoxamine[vitamin (vit)B6]] (biosynthesized from pyridoxal in vivo) is known to detoxify reactive carbonyl compounds (RCOs) via carbonyl-amine chemistry.Cellular removal of AGEs hinges largely upon the activity of the zinc metalloenzyme glyoxalase I (GLO1). We detected idiopathic carbonyl stress in a subpopulation of schizophrenia. We first found an interesting case carrying genetic defect of glyoxalase 1 (GLO1)that increased AGEs and decreased vitamin B6 since GLO1 detoxifies AGEs and vitamin B6 is carbonyl scavenger. We obtained 20% of patients showing carbonyl stress by the manner expanding concept of the case over the general schizophrenic patients. This manner can resolve the problem of research on schizophrenia derived from the heterogeneity of the disease. Genetic defect of GLO1 contributes to the stress by 5 time’s higher risk compared to that of intact gene. AGEs level was significantly correlated with negative symptoms of the patients. Pyridoxamine, active vitamin B6, could be the first medicine for negative symptoms of schizophrenia as most of the antipsychotic medicines are not effective for negative symptoms. We here present unique report of resolution of research difficulty due to heterogeneity of schizophrenia and possible discovery of the drug for negative symptoms of the disease.



Figure 1 . Plasma pentos idine accumulation and serum pyridoxal(vitamin B6) depletion.Levels of plasma pentos idine (A) and serum pyridoxal (B ) were analyzed us ing hig h-performance liquid chromatog raphy techniques .Values were compared using the Mann-Whitney U tes t (2 -tailed). Error bars indicate s tandard devi

References
Nishizawa D. et al. Mol Psychiatry 19(1):55-62, 2014
Ichikawa T. et al. Mol Genet Metab 105(1):103-109, 2012
Arai M. et al. Arch Gene Psychiatry 67:589-597, 2010
Doi N. et al. PLoS One 4(11):e7799, 2009
Hiroi N. et al. Proc Natl Acad Sci U S A.102:19132-19137,
2005
Sora I.et.al.Proc Natl Acad Sci U S A.98:5300-5305,2001
Lin Z. et al. FASEB J. 14(5):715-528, 2000

In April of 2011, three Tokyo Metropolitan Government-operated institutes, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Institute of Psychiatry and Tokyo Metropolitan Institute for Neuroscience, merged into one institute, The Tokyo Metropolitan Institute of Medical Science, and started its operation at the new location below.

2-1-6, Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
Tel: 81-3-5316-3100

Laboratories

The University of Tokyo
Graduate School of Frontier Sciences, The University of Tokyo

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