PPP2R2B Bβ1/Bβ2 Isoform and Role in Regulation of Cell Proliferation

Abstract

PPP2R2B (Bβ)為廣泛表現在腦部的去磷酸酶PP2A 的調控次單位。啟動子的差異使用及選擇性裁接，產生N 端相異的Bβ1 及Bβ2 兩種isoform，分別使PP2A 主要作用在細胞內不同部位。Bβ在神經細胞存活上扮演重要角色。Bβ1/Bβ2 表現的改變會影響PP2A 活性，進而導致神經退化性疾病。為檢視Bβ 調控的PP2A 在神經退化性疾病的角色，我們建立了誘導性Bβ1/Bβ2 細胞株。Myc標記的Bβ1、Bβ2 蛋白的誘導表現後，分別被標的至細胞質或粒線體。Bβ 細胞株的細胞週期分析顯示，在Bβ2 表現的細胞中，subG1 及G2/M 期顯著增加，並伴隨著顯著的細胞增生遲緩及抑制性磷酸化Cdc2 蛋白增加。我們的實驗結果顯示，抑制Bβ2 表現可能被發展為有潛能的治療策略，來治療與PP2A/ Bβ2 活性增加相關的神經退化性疾病。

PPP2R2B (Bβ) is an important regulator of protein phosphatase 2A (PP2A) activity in the brain. Through differential promoter usage and alternative splicing, two major isoforms Bβ1 and Bβ2 with divergent sub-cellular targeting N termini are produced. Bβ plays an important role in neuronal survival. Altered Bβ1/Bβ2 expression would be reflected by abnormal PP2A activity to predispose to neurodegenerative diseases. In this study we established inducible Bβ1/Bβ2 cell lines to investigate the role of Bβ-modulating PP2A in neuronal degeneration. The induced Myc-tagged Bβ1/Bβ2 proteins were mainly localized in cytoplasm and mitochondria, respectively. Cell cycle analysis of Bβ cell lines revealed a significant increase in the cell population at subG1 and G2/M phases in Bβ2-expressing cells, accompanying with significant reduced cell proliferation and increased inhibitory phosphorylation of cell division cycle 2. Taken together, these results suggest that inhibition of Bβ2 expression may be an attractive avenue for developing potential therapeutic strategies to treat neurodegenerative disordersrelated to increased PP2A/Bβ2 activity.