Department of Biochemistry &Molecular Biology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Tulane Cancer Center, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
Nat Commun. 2016 Dec 23;7:13755. doi: 10.1038/ncomms13755.
The tumour suppressor p53 transactivates the expression of its target genes to exert its functions. Here, we identify a pleckstrin homology domain-containing protein (PHLDB3)-encoding gene as a p53 target. PHLDB3 overexpression increases proliferation and restrains apoptosis of wild-type p53-harboring cancer cells by reducing p53 protein levels. PHLDB3 binds to MDM2 (mouse double minute 2 homolog) and facilitates MDM2-mediated ubiquitination and degradation of p53. Knockdown of PHLDB3 more efficiently inhibits the growth of mouse xenograft tumours derived from human colon cancer HCT116 cells that contain wild type p53 compared with p53-deficient HCT116 cells, and also sensitizes tumour cells to doxorubicin and 5-Fluorouracil. Analysis of cancer genomic databases reveals that PHLDB3 is amplified and/or highly expressed in numerous human cancers. Altogether, these results demonstrate that PHLDB3 promotes tumour growth by inactivating p53 in a negative feedback fashion and suggest PHLDB3 as a potential therapeutic target in various human cancers.
抑癌蛋白 p53 通过转录激活其靶基因来发挥作用。在这里，我们鉴定了一个含有 PH 结构域的蛋白（PHLDB3）编码基因为 p53 的靶基因。PHLDB3 的过表达通过降低 p53 蛋白水平，增加野生型 p53 携带的癌细胞的增殖并抑制细胞凋亡。PHLDB3 与 MDM2（鼠双微 2 同源物）结合，并促进 MDM2 介导的 p53 的泛素化和降解。与 p53 缺失的 HCT116 细胞相比，PHLDB3 的敲低更有效地抑制了含有野生型 p53 的人结肠癌 HCT116 细胞来源的小鼠异种移植瘤的生长，并且还使肿瘤细胞对阿霉素和 5-氟尿嘧啶敏感。对癌症基因组数据库的分析表明，PHLDB3 在许多人类癌症中扩增和/或高表达。总之，这些结果表明 PHLDB3 通过负反馈方式使 p53 失活来促进肿瘤生长，并提示 PHLDB3 可能成为各种人类癌症的潜在治疗靶点。
