TACC3於脂肪分化過程中之角色

Abstract

TACC蛋白質家族，最先是在癌症細胞中發現。TACC蛋白被認為與細胞生長和分化相關。TACC3是TACC家族蛋白其中一個成員，大量的表現在胚胎發育及脂肪分化中，然而TACC3在脂肪分化中確實的角色還是未知。GSK3是一個多功能的激酶，在脂肪細胞分化中也扮演一個重要的調控角色，最近由我們實驗室發現GSK3可以負向的調控TACC3蛋白質表現量，經由GSK3對TACC3磷酸化引發下游泛素化接合酶-SCFFbw2主導的泛素化-蛋白質酶體的代謝路徑降解TACC3。在本篇論文中我們探討TACC3在脂肪細胞分化中的角色以及在此分化過程中TACC3表現量是否經由GSK3激酶所調控。我們呈現TACC3蛋白在脂肪細胞分化前期有大量表現，然而隨後TACC3隨著分化時間遞減是脂肪細胞成熟所需的過程。此外TACC3對於脂肪分化中幾個主要的轉譯因子有負向的調控。當使用GSK3的抑制劑LiCl來抑制GSK3活性會造成TACC3蛋白的累積並降低脂肪細胞中主要轉錄因子的表現，造成油滴累積量的下降。我們更進一步呈現，使用shRNA降低TACC3的表現量能部份抵制LiCl對於脂肪分化的抑制進而增加脂肪細胞內油滴的產生。總而言之，我們的研究顯示TACC3在脂肪細胞成熟過程中擔任一個負向調控的角色。

Transforming acidic coiled-coil (TACC) family is a group of proteins containing common C-terminal acidic coiled-coil domain, firstly found in cancer cells. TACC proteins were hypothesized to be involved in cellular growth and differentiation. TACC3, one of TACC family members, is highly expressed during embryonic development and adipocyte differentiation. Currently, the role of TACC3 in adipogenesis is still unknown. GSK3, a multifunction kinase also important for adipocyte development, has recently identified in our lab to negatively regulate TACC3 protein stability by phosphorylation in association with ubiquitin-dependent degradation pathway via SCFFbw2 E3 ligases. Here, we asked whether TACC3 is involved in the differentiation process of adipocytes and whether TACC3 stability is regulated by GSK3 in the process. We demonstrated that the level of TACC3 protein can be induced in early phase and declined during differentiation process of 3T3-L1 in late stage, which is essential for adipogenesis. TACC3 attenuated the levels of several master adipogenic transcription factors. Inhibition of GSK3 by LiCl resulted in an increase of TACC3 protein level, correlating with a suppression of lipid formation. In addition, depletion of TACC3 level by shRNA led to partially abolish the repressive effect of LiCl on adipogenesis. These results suggest that TACC3 plays a negatively regulatory role in adipocyte differentiation.