Human homolog of Drosophila tumor suppressor Scribble negatively regulates cell-cycle progression from G1 to S phase by localizing at the basolateral membrane in epithelial cells
Human homolog of Drosophila tumor suppressor Scribble negatively regulates cell-cycle progression from G1 to S phase by localizing at the basolateral membrane in epithelial cells
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DOI：
10.1111/j.1349-7006.2006.00315.x
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发表时间：
2006-11-01
期刊：
影响因子：
5.7
通讯作者：
Taketani, Yuji
中科院分区：
文献类型：
--
作者：
Nagasaka, Kazunori;Nakagawa, Shunsuke;Taketani, Yuji
果蝇肿瘤抑制因子Scribble已被鉴定为上皮细胞的顶端-基底外侧极性决定因素。人类与果蝇Scribble的同源物hScribble(HScrib)已被鉴定为人乳头瘤病毒E6靶向的蛋白质，依赖于细胞泛素-蛋白质连接酶E6AP介导的泛素降解。人类Scribble被归类为LAP蛋白，具有富含亮氨酸的重复序列(LRR)和PDZ结构域。我们研究了hScrib是否参与了细胞周期调节和上皮细胞的增殖控制，hScrib被认为在基于其果蝇同源基因的数据中具有决定极性的作用。HScrib基因可抑制细胞周期从G1期进入S期，并分别上调和下调结肠腺瘤性息肉病和细胞周期蛋白A和细胞周期蛋白D的表达。小干扰RNA抑制hScrib的表达，使细胞周期从G1期进入S期。我们探索了hScrib的功能结构域图谱，以揭示hScrib的哪些结构域对其细胞增殖控制和基底膜的定位至关重要。我们发现，LRRs和PDZ结构域1对于hScrib通过阻断细胞周期进程来抑制细胞生长和保持其正确的定位是必不可少的。这些数据表明，hScrib的基侧膜定位与其增殖控制密切相关。我们的发现提示hScrib可能通过LRRs和PDZ结构域定位于上皮细胞基底膜，参与负调控细胞增殖的信号转导。
Drosophila tumor suppressor Scribble has been identified as an apical-basolateral polarity determinant in epithelia. A human homolog of Drosophila Scribble, human Scribble (hScrib), has been identified as a protein targeted by human papillomavirus E6 for the ubiquitin-mediated degradation dependent on E6AP, a cellular ubiquitin-protein ligase. Human Scribble is classified as a LAP protein, having leucine-rich repeats (LRRs) and PDZ domains. We investigated whether hScrib, which is thought to have a role in polarity determination based on the data of its Drosophila homolog, is involved in cell-cycle regulation and proliferation control of epithelia. Transfection of hScrib inhibits cell-cycle progression from G1 to S phase, and it up- and down-regulates expression of adenomatous polyposis coli and cyclins A and D1, respectively. Knockdown of hScrib expression by siRNA leads to cell-cycle progression from G1 to S phase. We explored functional domain mapping to reveal which domains of hScrib are critical for its cellular proliferation control and localization at the basolateral membrane. We found that LRRs and PDZ domain 1 are indispensable for hScrib to inhibit cell growth by blocking cell-cycle progression and to keep its proper localization. These data indicate that basolateral membrane localization of hScrib is closely related to its proliferation control. Our findings suggest the possibility that hScrib is involved in signal transduction to negatively regulate cell proliferation by localizing at the basolateral membrane of epithelial cells through LRRs and PDZ domains.