Verga Falzacappa Cecilia, Petrucci Eleonora, Patriarca Valentina, Michienzi Simona, Stigliano Antonio, Brunetti Ercole, Toscano Vincenzo, Misiti Silvia
Chair of Endocrinology, II Faculty of Medicine, University La Sapienza, Rome, Italy.
J Mol Endocrinol. 2007 Feb;38(1-2):221-33. doi: 10.1677/jme.1.02166.
It has recently been recognized that thyroid hormones may rapidly generate biological responses by non-genomic mechanisms that are unaffected by inhibitors of transcription and translation. The signal transduction pathways underlying these effects are just beginning to be defined. We demonstrated that thyroid hormone T3 rapidly induces Akt activation in pancreatic beta cells rRINm5F and hCM via thyroid hormone receptor (TR) beta1. The phosphorylation of Akt was T3 specific and dependent. Coimmunoprecipitation and colocalization experiments revealed that the phosphatidylinositol 3 kinase (PI3K) p85alpha subunit and the thyroid receptor beta1 were able to form a complex at the cytoplasmic level in both the cell lines, suggesting that a 'cytoplasmic TRbeta1' was implicated. Moreover, we evidenced that T3 treatment was able to induce kinase activity of the TRbeta1-associated PI3K. The silencing of TRbeta1 expression through RNAi confirmed this receptor to be crucial for the T3-induced activation of Akt. This action involved a T3-induced nuclear translocation of activated Akt, as demonstrated by confocal immunofluorescence. In summary, T3 is able to specifically activate Akt in the islet beta cells rRINm5F and hCM through the interaction between TRbeta1 and PI3K p85alpha, demonstrating the involvement of TRbeta1 in this novel T3 non-genomic action in islet beta cells.
最近人们认识到，甲状腺激素可能通过不受转录和翻译抑制剂影响的非基因组机制快速产生生物学反应。这些效应背后的信号转导途径才刚刚开始被确定。我们证明，甲状腺激素T3通过甲状腺激素受体（TR）β1在胰腺β细胞rRINm5F和hCM中快速诱导Akt激活。Akt的磷酸化具有T3特异性且具有依赖性。免疫共沉淀和共定位实验表明，磷脂酰肌醇3激酶（PI3K）p85α亚基和甲状腺受体β1能够在两种细胞系的细胞质水平形成复合物，这表明存在“细胞质TRβ1”。此外，我们证明T3处理能够诱导与TRβ1相关的PI3K的激酶活性。通过RNAi沉默TRβ1表达证实该受体对T3诱导的Akt激活至关重要。共聚焦免疫荧光显示，这一作用涉及T3诱导的活化Akt的核转位。总之，T3能够通过TRβ1与PI3K p85α之间的相互作用在胰岛β细胞rRINm5F和hCM中特异性激活Akt，证明TRβ1参与了胰岛β细胞中这种新的T3非基因组作用。
