Pleckstrin homology domain-containing protein PHLDB3 supports cancer growth via a negative feedback loop involving p53

被引：30

作者：

Chao, Tengfei ^{[1
,2
,3
]}

Zhou, Xiang ^{[1
,2
,4
,5
]}

Cao, Bo ^{[1
,2
]}

Liao, Peng ^{[1
,2
]}

Liu, Hongbing ^{[1
]}

Chen, Yun ^{[1
]}

Park, Hee-Won ^{[1
]}

Zeng, Shelya X. ^{[1
,2
]}

Lu, Hua ^{[1
,2
,6
]}

机构：

[1] Tulane Univ, Sch Med, Dept Biochem & Mol Biol, 1430 Tulane Ave, New Orleans, LA 70112 USA

[2] Tulane Univ, Sch Med, Tulane Canc Ctr, 1430 Tulane Ave, New Orleans, LA 70112 USA

[3] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Oncol, Wuhan 430030, Peoples R China

[4] Fudan Univ, Shanghai Canc Ctr, Shanghai 200032, Peoples R China

[5] Fudan Univ, Inst Biomed Sci, Shanghai 200032, Peoples R China

[6] Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

中国国家自然科学基金;

关键词：

TUMOR-SUPPRESSOR; MDM2; COMPLEX; SCREEN; UBIQUITYLATION; DEGRADATION; INHIBITION; REGULATOR; PROFILES; PATHWAYS;

D O I：

10.1038/ncomms13755

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：12

共 43 条

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ELIFE, 2016, 5

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