Jun-ichiro Mori

Functional Interaction between Oct-1 and Retinoid X Receptor

The retinoid X receptor (RXR) is a member of the nuclear hormone receptor superfamily and heterodimerizes with a variety of other family members such as the thyroid hormone receptor (TR),1 retinoic acid receptor, vitamin D receptor, and peroxisome proliferator-activated receptor. Therefore, RXR is supposed to play a key role in a ligand-dependent regulation of gene transcription by nuclear receptors. In this study, we have identified the octamer-binding transcription factor-1 (Oct-1) as a novel interaction factor of RXR. In vitro pull-down assays using RXR deletion mutants showed that the interaction surfaces were located in the region encompassing the DNA binding domain (C domain) and the hinge domain (D domain) of RXR. We also showed that RXR interacted with the POU homeodomain but not with the POU-specific domain of Oct-1. Gel shift analysis revealed that Oct-1 reduced the binding of TR/RXR heterodimers to the thyroid hormone response element (TRE). In transient transfection assays using COS1 cells, Oct-1 repressed the T3-dependent transcriptional activity of TR/RXR heterodimers, consistent with in vitro DNA binding data; however, transcriptional activation by Gal4-TR(LBD) (LBD, ligand binding domain), which lacks its own DNA binding domain but retains responsiveness to T3, was not influenced by Oct-1. These results suggest that Oct-1 functionally interacts with RXR and negatively regulates the nuclear receptor signaling pathway by altering the DNA binding ability of the receptors.

The role of hinge domain in heterodimerization and specific DNA recognition by nuclear receptors.

Four structural domains are characteristic of the members of the nuclear receptor superfamily. The hinge (D) domain which is located between the DNA binding (C) domain and the ligand binding (EF) domain, is less conserved among the nuclear receptors. In this study, we investigated the effects of the D domain on receptor function with regard to ligand binding, protein-protein interaction and DNA recognition. We found that EF domain of TR lacked T3 binding activity and additional D domain was required for its ligand binding. Using pull down assays and two-hybrid assays, we also demonstrated that the EF domain of TR did not dimerize with TR or RXR in solution, while the DEF domain was able to homo-and heterodimerize with RXR. In contrast, the RXR EF domain alone was able to heterodimerize with TR. The D domain of TR is required but that of RXR is not necessary for the interaction. We further demonstrated that the D domain was required for receptor specific DNA recognition. The ABC domain of vitamin D receptor (VDR) and TR(DEF) chimeric receptor could not bind to VDR response element (VDRE). Addition of own D domain of VDR to the ABC domain enables the chimeric receptor to bind VDRE and transactivate. The D domain of TR cannot substitute for that of VDR in context of specific DNA recognition. These data suggest that the D domain is important to maintain the integrity of the functional structure of the nuclear receptors.

3,5,3′-Triiodo-l-Thyronine Potentiates All-Trans-Retinoic Acid-Induced Apoptosis during Differentiation of the Promyeloleukemic Cell HL-60

Although the programmed cell death mediated by thyroid hormone is not well evaluated in mammalian cells, thyroid hormone plays a crucial role in differentiation of the cells during the metamorphosis of Xenopus, suggesting that thyroid hormone has the potential ability to induce the apoptosis. To investigate the thyroid hormone-inducible apoptosis, we cultured HL-60 cells with various amounts of all-trans-retinoic acid (RA) and l-T3. T3 alone did not induce the apoptosis of the cells. T3, however, suppressed the proliferation of cells in the presence of RA. DNA ladder and microscopical examination showed that the reduction of cell number was due to the apoptosis induced by RA. These findings suggested that T3 affects the apoptotic process during the differentiation of HL-60 cells by RA. T3-inducible apoptosis may require the factors augmented by RA in HL-60 cells.

Tobacco Price Increase and Smoking Cessation in Japan, a Developed Country With Affordable Tobacco: A National Population-Based Observational Study

Background Longitudinal assessment of the impact of tobacco price on smoking cessation is scarce. Our objective was to investigate the effect of a price increase in October 2010 on cessation rates according to gender, age, socioeconomic status, and level of tobacco dependence in Japan. Methods We used longitudinal data linkage of two nationally representative studies and followed 2702 smokers for assessment of their cessation status. The odds ratios (ORs) for cessation were calculated using logistic regression. To estimate the impact of the 2010 tobacco price increase on cessation, data from 2007 were used as a reference category. Results Overall cessation rates significantly increased from 2007 to 2010, from 3.7% to 10.7% for men and from 9.9% to 16.3% for women. Cessation rates were 9.3% for men who smoked 1–10 cigarettes per day, 2.7% for men who smoked 11–20 cigarettes per day, and 2.0% for men who smoked more than 20 cigarettes per day in 2007. These rates increased to 15.5%, 10.0%, and 8.0%, respectively, in 2010. The impact was stronger among subjects who smoked more than 11 cigarettes per day than those who smoked 1–10 cigarettes per day in both sexes: ORs for 2010 were 4.04 for those smoking 11–20 cigarettes per day, 4.26 for those smoking more than 20 cigarettes per day, and 1.80 for those smoking 1–10 cigarettes per day in the main model in men. There were no obvious differences in the relationship between tobacco price increase and smoking cessation across age and household expenditure groups. Conclusions The tobacco price increase in Japan had a significant impact on smoking cessation in both sexes, especially among heavy smokers, with no clear difference in effect by socio-demographic status.

Mentoring the next generation of physician-scientists in Japan: a cross-sectional survey of mentees in six academic medical centers

BackgroundPhysician-scientists play key roles in biomedical research across the globe, yet prior studies have found that it is increasingly difficult to recruit and retain physician-scientists in research careers. Access to quality research mentorship may help to ameliorate this problem in the U.S., but there is virtually no information on mentoring in academic medicine in Japan. We conducted a survey to determine the availability and quality of mentoring relationships for trainee physician-scientists in Japan.MethodsWe surveyed 1700 physician-scientists in post-graduate research training programs in 6 academic medical centers in Japan about mentorship characteristics, mentee perceptions of the mentoring relationship, and attitudes about career development.ResultsA total of 683 potential physician-scientist mentees completed the survey. Most reported that they had a departmental mentor (91%) with whom they met at least once a month; 48% reported that they were very satisfied with the mentoring available to them. Mentoring pairs were usually initiated by the mentor (85% of the time); respondents identified translational research skills (55%) and grant writing (50%) as unmet needs. Mentoring concerning long-term career planning was significantly associated with the intention to pursue research careers, however this was also identified by some mentees as an unmet need (35% desired assistance; 15% reported receiving it).ConclusionsMore emphasis and formal training in career mentorship may help to support Japanese physician-scientist mentees to develop a sense of self-efficacy to pursue and stay in research careers.

Multiple Endocrine Neoplasia Type 1 Concomitant with Prader-Willi Syndrome: Case Report and Genetic Diagnosis

A case of multiple endocrine neoplasia type 1 (MEN 1) accompanied with Prader-Willi syndrome (PWS) was reported. Diagnosis of both diseases have been genetically confirmed. Delay in the diagnosis and management for PWS made surgery for endocrine tumors difficult. This is the first report on the concomitance of MEN 1 with PWS.