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Department of Biochemical Genetics,Medical Research Institute,Tokyo Medical and Dental Univ.

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Scope of Research@

Transcriptional regulation is one of the most important processes by which genome information is expressed from DNA to mRNA to protein.  The faithful synthesis of mRNA is achieved by transcriptional machinery comprised of RNA polymerase II, basal factors and many other protein factors, whose dysfunction is implicated in various human diseases.  Our research interest is focused on the basic mechanism of transcription cycle and implication of early response transcription factors in determining cell fate in stress response.  Our lab also studies on the control of cell cycle of terminally differentiated cells and its re-activation to provide novel regeneration therapy



Research1
To provide novel paradigm of transcriptional regulation

Transcription proceeds from initiation to elongation to termination, and to recycling of another transcription when gene expression is activated.  Among many protein factors, TFIIF functions as both initiation and elongation factor whereas elongin A functions during elongation phase and its dys-regulation may play role in von Hippel-Lindau disease.  FCP1, a TFIIF-activated CTD phosphatase, plays role in recycling, and its deficiency causes a genetic disease called CCFDN.  We focus on these factors in order to understand function of these factors in transcription cycle and their implication in human disease, such as transcription syndrome.

1jEstablishment of cells stably expressing tagged-TFIIF, -Elongin A, -FCP1 and analysis of complex during transcription cycle
2jStudies on elongin A null MEF
3jStudies on trithorax group of histone methyltransferase using gene knock-out mouse model 


Transcription cycle and transcription syndrome

RNA polymerase II transcription cycle contains initiation, elongation, termination and recycling phases, all of which involves chromatin remodeling. Its disorder causes various diseases called transcription syndrome


Research2
To understand role of transcription factor in cell fate determination

Dual role activiting transcription factor(ATF)3 in cellI fate determination

Cells determine their life or death in response to environment.  Activating transcription factor (ATF) 3 is an early response gene and functions in cell death, survival and proliferation.  Despite many reports that ATF3 is a death factor, we recently found that it is also survival factor and is a target of c-Myc in cell proliferation.  On the other hands, a splice variant of ATF3, ATF3deltaZip2, inhibits NF-kB activity, thus functioning as pro-apoptosis factor in stress response.  Our aim of ATF3 research is to understand dual role of ATF3 in oncogenesis, anticancer therapy, and various stress response, and to search for clinical applicability to cell fate control.   

‚PjRole in cell proliferation

ATF3 is a target of c-myc oncogene and has a positive effect on proliferation of c-myc null cells in serum response.  It might be a mediator of c-Myc in oncogenesis and expansion of cancer stem cells, also implicated in cancer cell dormancy. 





c-Myc/ATF3 pathway in cell
cycle control

ATF3 is a targe y of protooncogene c-myc and
rescues the impaired cell cycle of c-myc-null cells








2jRole in cell death
ATF3 also plays cell detrimental effect in stress response to UV, TNF, or oxidative and reductive stress.  As one mechanism for this, we found that a splice variant, ATF3deltaZip2, antagonizes anti-apoptosis of NF-kB.  Regulation of ATF3 by stress-induced alternative splicing may be implicated in cell death in many stress response





Role of a spliced variant ATF3deltaZip2 in cell death

Zip2 antagonizes anti-apoptosis of NF-kB and functions as
a proaoptotic factor
















Research3
Re-activation of cell cycle of terminally differentiated cardiomyocytes

Cardiac cells cease to proliferate after birth and enter the terminal differentiation, thus can not regenerate when they are damaged by cardiac infarction or cardiomyopathy.  We have succeeded in re-activating cell cycle of cardiac cells through forced expression of cyclin D1, an accelerator, and degradation of p27, a brake of cell cycle.  Our lab aims to provide a novel technique for re-activating cell cycle of terminally differentiated cells, such as cardiomyocytes

1.Cell cycle barriers of cardiomyocytes

One barrier is that an accelerator cyclin D1 is not expressed in nuclei by mechanism(s) not identified yet.  Another is that p27, a brake of cell cycle progression, is not degraded in cardiomyocytes. The combined effect of, at least these two barriers, locks cardiac cells to enter cell cycle.  Release of these steps successfully re-activates cell proliferation of cardiac cells.

The first barrier
Cyclin D1 can not be expressed in nuclei of cardiomyocytes.  Thus, forced nuclear expression of cyclin D1 causes Rb phosphorylation and DNA synthesis, and finally cell cycle progression.


The second barrier
Cell cycle progression by nuclear cyclin D1 is transient and limited due to early accumutation of p27.  Degradation of p27 by Skp2 or siRNA results in more stable cell proliferation.



Ongoing projects

@@1.To find out another cell cycle barrier(s)
2.Re-activation of cell cycle in cardiac tissue in situ and the cardio-protective effect
3.Research using human cardiac cells (approved by the University Committee for use of human source)