Functional analysis of a novel signaling cascade activated by thyroid hormone: Role of PI3 kinase→PKB→mTOR→ZAKI-4αactivation by thyroid hormone
Functional analysis of a novel signaling cascade activated by thyroid hormone: Role of PI3 kinase→PKB→mTOR→ZAKI-4αactivation by thyroid hormone
批准号:
16390269
负责人:
SEO Hisao
金额:
$8.9万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (B)
财政年份:
2004
资助国家:
日本
项目状态:
已结题
起止时间:
2004 至 2006
中文摘要
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英文摘要
Thyroid hormone (TH) is essential for normal development, growth and metabolism. Its effects are mediated through triiodothyronine (T_3), which acts as a ligand for the TH receptors (TRs). In the classical model of genes positively regulated by TH, the TR first binds as a heterodimer or homodimer on TH response elements (TRE) located in the promoter regions of target genes, where it interacts with corepressors. Upon ligand binding, the TR homodimers are dissociated in favor of heterodimer formation with the retinoid-X receptor (RXR), resulting in release of the corepressors and recruitment of coactivators. This new complex attracts a large number of proteins which engage the RNA polymerase II in the transcription of the targeted gene. In addition to the classical, "nuclear" mode of TH action, we demonstrated that TH also activates PI3K-Akt signaling pathway rapidly through a non-genomic mechanism. It was found that 1) TH treatment induced sequential phosphorylation and activation of th … More e serine/threonine kinase Akt, the mammalian target of rapamycin (mTOR) and its substrate p70^<S6K> and 2) phosphorylation of these proteins was abrogated by both PI3K inhibitors, LY294002 and wortmannin, and by a dominant negative regulatory subunit of PI3K (p85a). This TH action is very rapid and independent of protein synthesis, suggesting that it does not involve the typical nuclear action of TR. It is of note that this rapid TH action was abrogated by the introduction of a dominant negative TRP (TRG345R) into the cells expressing the wild type TRβ, indicating the participation of TRβ. It was demonstrated that TRβ directly interacts with the regulatory subunit of PI3K, p85a in human skin fibroblasts. The interaction is independent of ligand binding, while PI3K can be activated only in the presence of TH. We and others identified several genes under the control of this action, including ZAKI-4a, hypoxia-inducible factor-la, glucose transporter 1, phosphofructokinase, and the monocarboxylate transporter 4. ZAKI-4 gene was originally identified by us as a thyroid hormone (TH) responsive gene which locates on human chromosome 6. We later found that three transcripts, a, β1 and β2, were generated by the single ZAKI-4 gene through differential splicing. The β1 and β2 isoforms encode the same protein product ZAKI-4β, which shares the common carboxyl terminal region with ZAKI-4a. Both ZAKI-4a and β belong to a family of small structurally related proteins which bind to, and down-regulate the activity of calcineurin (protein phosphatase 2B). It was demonstrated in human and rodents that the expression of only a isoform is upregulated. by TH. Since it is known that calcineurin is involved in neuronal plasticity, TH may play the role in neuronal plasticity through regulating calcineurin activity. Less
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DOI:
10.1016/j.bbrc.2006.01.052
发表时间:
2006-03-24
期刊:
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子:
3.1
作者:
[Murakami, H, Murakami, R, Murohara, T]
通讯作者:
Murohara, T
甲状腺刺激ホルモンと甲状腺ホルモン
促甲状腺激素和甲状腺激素
DOI:
--
发表时间:
2005
期刊:
影响因子:
--
作者:
[WAKABAYASHI K, KAMBE F, CAO X, et al., YOSHIDA J, SEO H, 妹尾 久雄, 妹尾 久雄]
通讯作者:
妹尾 久雄
標準生理学(第6版)
标准生理学(第六版)
DOI:
--
发表时间:
2005
期刊:
影响因子:
--
作者:
[WAKABAYASHI K, KAMBE F, CAO X, et al., YOSHIDA J, SEO H, 妹尾 久雄, 妹尾 久雄, 妹尾 久雄]
通讯作者:
妹尾 久雄
DOI:
10.1038/sj.onc.1207778
发表时间:
2004-09-09
期刊:
ONCOGENE
影响因子:
8
作者:
[Wakabayashi, K, Kambe, F, Seo, H]
通讯作者:
Seo, H
DOI:
10.1210/en.2005-1426
发表时间:
2006-06-01
期刊:
ENDOCRINOLOGY
影响因子:
4.8
作者:
[Lu, Xiuli, Kambe, Fukushi, Seo, Hisao]
通讯作者:
Seo, Hisao
共 14 条
Crosstalk between Ca^<2+>-calcineurin-pathway and thyroid hormone action
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批准号:13470217
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项目类别:Grant-in-Aid for Scientific Research (B)
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资助金额:$5.18万
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财政年份:2001
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负责人:SEO Hisao
-
依托单位:
FUNCTION OF COFACTORS MODIFYING THYROID HORMONE RECEPTOR FUNCTION
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批准号:10470226
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项目类别:Grant-in-Aid for Scientific Research (B).
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资助金额:$3.78万
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财政年份:1998
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负责人:SEO Hisao
-
依托单位:
REGULATION OF THYROID FUNCTION BY TRANSCRIPTION FACTOR NF-kappaB
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批准号:07457222
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项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$3.46万
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财政年份:1995
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负责人:SEO Hisao
-
依托单位:
INTERFERON-b GENE THERAPY FOR VIRAL HEPATITIS
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批准号:05557033
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项目类别:Grant-in-Aid for Developmental Scientific Research (B)
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资助金额:$4.48万
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财政年份:1993
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负责人:SEO Hisao
-
依托单位:
Cloning of homeobox genes involved in the differentiation of placental cells producing peptide hormones
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批准号:04454559
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项目类别:Grant-in-Aid for General Scientific Research (B)
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资助金额:$4.29万
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财政年份:1992
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负责人:SEO Hisao
-
依托单位:
Study on the Physiological Role of Carbohydrate Residues in Thyroxine Binding Globulin Using Introduction of its Gene by Transfection
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批准号:63480268
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项目类别:Grant-in-Aid for General Scientific Research (B)
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资助金额:$3.07万
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财政年份:1988
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负责人:SEO Hisao
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依托单位:
Thyroxine-binding globulin, Molecular biology of the gene and its abnormal expressions
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批准号:60480267
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项目类别:Grant-in-Aid for General Scientific Research (B)
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资助金额:$2.5万
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财政年份:1985
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负责人:SEO Hisao
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依托单位:
海外基金