Laboratory of Fundamental Oncology, National Cancer Center Research Institute, Tokyo, Japan.
Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Cancer Sci. 2018 Nov;109(11):3532-3542. doi: 10.1111/cas.13796. Epub 2018 Oct 13.
The PHLDA family (pleckstrin homology-like domain family) of genes consists of 3 members: PHLDA1, 2, and 3. Both PHLDA3 and PHLDA2 are phosphatidylinositol (PIP) binding proteins and function as repressors of Akt. They have tumor suppressive functions, mainly through Akt inhibition. Several reports suggest that PHLDA1 also has a tumor suppressive function; however, the precise molecular functions of PHLDA1 remain to be elucidated. Through a comprehensive screen for p53 target genes, we identified PHLDA1 as a novel p53 target, and we show that PHLDA1 has the ability to repress Akt in a manner similar to that of PHLDA3 and PHLDA2. PHLDA1 has a so-called split PH domain in which the PH domain is divided into an N-terminal (β sheets 1-3) and a C-terminal (β sheets 4-7 and an α-helix) portions. We show that the PH domain of PHLDA1 is responsible for its localization to the plasma membrane and binding to phosphatidylinositol. We also show that the function of the PH domain is essential for Akt repression. In addition, PHLDA1 expression analysis suggests that PHLDA1 has a tumor suppressive function in breast and ovarian cancers.
PHLDA 家族（pleckstrin homology-like domain family）由 3 个成员组成：PHLDA1、2 和 3。PHLDA3 和 PHLDA2 都是磷酸肌醇（PIP）结合蛋白，作为 Akt 的抑制剂发挥作用。它们具有肿瘤抑制功能，主要通过抑制 Akt。有几项报告表明 PHLDA1 也具有肿瘤抑制功能；然而，PHLDA1 的精确分子功能仍有待阐明。通过对 p53 靶基因的全面筛选，我们将 PHLDA1 鉴定为一种新型的 p53 靶基因，我们表明 PHLDA1 具有类似于 PHLDA3 和 PHLDA2 的抑制 Akt 的能力。PHLDA1 具有所谓的分裂 PH 结构域，其中 PH 结构域分为 N 端（β 片层 1-3）和 C 端（β 片层 4-7 和一个 α 螺旋）部分。我们表明，PHLDA1 的 PH 结构域负责其定位于质膜并与磷酸肌醇结合。我们还表明，PH 结构域的功能对于 Akt 抑制至关重要。此外，PHLDA1 表达分析表明，PHLDA1 在乳腺癌和卵巢癌中具有肿瘤抑制功能。
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