Biomedical subjects

Yasuji Yamamoto

Publications and source records attributed to Yasuji Yamamoto.

6 recordsLinked to original sources

PubMed2005

Polymorphism of the regulatory region of the presenilin-2 gene in sporadic Alzheimer's disease: a case-control study.

OBJECTIVE: presenilin-2 is one of the causative genes for familial Alzheimer's disease, and the apolipoprotein E epsilon4 allele is a major genetic risk factor for late-onset and sporadic early-onset Alzheimer's disease. Polymorphism of the regulatory region of presenilin-2 has recently been reported to be associated with sporadic Alzheimer's disease in a Russian population. The purpose of this study was to determine whether Alzheimer's disease is associated with the presenilin-2 gene polymorphism and the apolipoprotein E genotype in an extended case-control study. METHODS: We examined 230 patients with Alzheimer's disease, along with an equal number of age- and sex-matched controls from the same community, in a Japanese population by using a Chi-square test for homogeneity and a logistic regression analysis. RESULTS: The presenilin-2 polymorphism frequencies were similar in early-onset Alzheimer's disease patients (0.17) and younger controls (0.15), and in late-onset Alzheimer's disease (0.20) and elderly controls (0.20). We found no evidence for an association between the presenilin-2 polymorphism and the apolipoprotein E epsilon4 allele. CONCLUSIONS: Our results fail to support an association of presenilin-2 gene polymorphism with Alzheimer's disease. The discrepancy between our results and the results of the Russian study appear to be due to racial differences.

Adult↗

PubMed2005

TAS-108, a novel oral steroidal antiestrogenic agent, is a pure antagonist on estrogen receptor alpha and a partial agonist on estrogen receptor beta with low uterotrophic effect.

PURPOSE: Investigators are currently conducting phase II trials on TAS-108, a novel oral steroidal antiestrogenic agent. The purpose of this study is to investigate the molecular and pharmacologic properties of TAS-108 compared with other antiestrogenic agents such as tamoxifen,raloxifene, and fulvestrant. EXPERIMENTAL DESIGN: The antagonistic or agonistic activities of these agents against both estrogen receptors (ER) alpha and beta were compared in the reporter assay systems. Their effects on the uterus were evaluated in ovariectomized rat models. The antitumor activity of TAS-108 given p.o. was evaluated in both dimethylbenzanthracene-induced mammary tumor model and human breast cancer MCF-7 cell line xenografts. RESULTS: TAS-108 inhibited the transactivation of ERalpha under the presence of 17beta-estradiol (E2) and did not induce the transactivation of ERalpha in the absence of E2, unlike the agonistic activity of tamoxifen. On the other hand, it exhibited the most agonistic activity on ERbeta among the antiestrogenic agents tested. When given p.o. in the ovariectomized rat, TAS-108 showed a much weaker estrogenic effect on utterine weight compared to tamoxifen, or with similar levels of raloxifene, a selective estrogen receptor modulator. Also, TAS-108 strongly inhibited tumor growth in dimethylbenzanthracene-induced mammary carcinomain the rat, the endogenous E2 model, at a dosage of 1 to 3 mg/kg/day. It also inhibited high exogenous E2, inducing tumor growth against MCF-7 xenografts at a dosage of 1 mg/kg/day without any toxic manifestation. CONCLUSIONS: Taken together, p.o. treatment with TAS-108 has a novel mode of action on ERs and inhibits E2-dependent tumor growth with little uterotrophic effect.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2003

Both N- and C-terminal transactivation functions of DNA-bound ERalpha are blocked by a novel synthetic estrogen ligand.

Estrogen receptors (ERs) play a central role in the diverse actions of estrogen. A number of synthetic ER ligands have been generated that can modulate various ER functions. Here we show that TAS-108, representing a novel class of synthetic ER ligands, blocked both ER transactivation functions without inhibiting DNA-binding activity. A transient expression assay showed that similar to ICI182,780, TAS-108 exhibited pure antagonistic activity as it blocked both the N-terminal AF-1 and C-terminal AF-2 transactivation functions. However, unlike ICI182,780, TAS-108 promoted the recruitment of the SMRT co-repressor that abolished ER transactivation function without inhibition of the ability of ERalpha to bind to its target DNA. Both TAS-108 and ICI182,780 acted as antagonists for the transactivation functions of the D351Y mutant, derived from tamoxifen-resistant breast cancer cells, while estrogen and known selective estrogen receptor modulators (SERMs), 4-OH tamoxifen and raloxifene, stimulated D351Y-mediated transcription. Thus, our findings indicated that TAS-108 acts as a novel estrogen antagonist that recruits co-repressors to ERs without AF-1 activation or prevention of DNA binding. Therefore, TAS-108 may be effective against tamoxifen-resistant breast cancer via a different mechanism than that for ICI182,780.

Animals↗

PubMed2003

Modulation of oestrogen receptor signalling by association with the activated dioxin receptor.

Environmental contaminants affect a wide variety of biological events in many species. Dioxins are typical environmental contaminants that exert adverse oestrogen-related effects. Although their anti-oestrogenic actions are well described, dioxins can also induce endometriosis and oestrogen-dependent tumours, implying possible oestrogenic effects. However, the molecular mechanism underlying oestrogen-related actions of dioxins remains largely unknown. A heterodimer of the dioxin receptor (AhR) and Arnt, which are basic helix-loop-helix/PAS-family transcription factors, mediates most of the toxic effects of dioxins. Here we show that the agonist-activated AhR/Arnt heterodimer directly associates with oestrogen receptors ER-alpha and ER-beta. This association results in the recruitment of unliganded ER and the co-activator p300 to oestrogen-responsive gene promoters, leading to activation of transcription and oestrogenic effects. The function of liganded ER is attenuated. Oestrogenic actions of AhR agonists were detected in wild-type ovariectomized mouse uteri, but were absent in AhR-/- or ER-alpha-/- ovariectomized mice. Our findings suggest a novel mechanism by which ER-mediated oestrogen signalling is modulated by a co-regulatory-like function of activated AhR/Arnt, giving rise to adverse oestrogen-related actions of dioxin-type environmental contaminants.

Animals↗

PubMed2003

Full activation of estrogen receptor alpha activation function-1 induces proliferation of breast cancer cells.

The effects of estrogen and anti-estrogen are mediated through the estrogen receptors (ER) alpha and beta, which function as ligand-induced transcriptional factors. Recently, one of the phthalate esters, n-butylbenzyl phthalate (BBP), has been shown to induce estrogen receptor-mediated responses. By using the truncated types of ER mutants, we revealed that activation function-1 (AF-1) activity was necessary for the BBP-dependent transactivation function of ERalpha. AF-1 is also known to be responsible for the partial agonistic activity of tamoxifen. Whereas tamoxifen exhibits an anti-estrogenic effect on proliferation of the MCF-7 breast cancer cell line, BBP showed an estrogenic effect on MCF-7 to stimulate proliferation. In vivo and in vitro binding assays revealed that whereas 4-hydroxytamoxifen (OHT) induced binding of ERalpha to both an AF-1 coactivator complex (p68/p72 and p300) and corepressor complexes (N-CoR/SMRT), BBP selectively enhanced the binding to the AF-1 coactivators. We also showed that the transcriptional activity of OHT-bound ERalpha was modulated by the ratio between the AF-1 coactivator and corepressor complexes. Expression of a dominant-negative type of N-CoR inhibited the interaction between OHT-bound ERalpha and N-CoR/SMRT and enhanced the transcriptional activity of OHT-bound ERalpha. Furthermore, the cell growth of MCF-7 stably expressing the dominant-negative type of N-CoR was enhanced by the addition of OHT. These results indicated that fully activated AF-1 induces the stimulation of breast cancer growth and that the ratio between AF-1 coactivators and corepressors plays a key role to prevent proliferation of tumor by tamoxifen.

3T3 Cells↗

PubMed2002

Nuclear receptor function requires a TFTC-type histone acetyl transferase complex.

Nuclear receptors (NRs) regulate transcription in a ligand-dependent way through two types of coactivator complexes: the p160/CBP histone acetyl transferase (HAT) complex and the DRIP/TRAP/SMCC complex without HAT activity. Here we identified a large human (h) coactivator complex necessary for the estrogen receptor alpha (ERalpha) transactivation. This complex contains the GCN5 HAT, the c-Myc interacting protein TRRAP/PAF400, TAF(II)30, and other subunits. Similarly to known TFTC (TBP-free TAF(II)-containing)-type HAT complexes (hTFTC, hPCAF, and hSTAGA), TRRP directly interacted with liganded ER alpha, or other NRs. ER alpha transactivation was enhanced by the purified complex in vitro. Antisense TRRAP RNA inhibited estrogen-dependent cell growth of breast cancer cells. Thus, the isolated TFTC-type HAT complex acts as a third class of coactivator complex for NR function.

Acetyltransferases↗