RDIVpSGP motif of ASPP2 binds to 14-3-3 and enhances ASPP2/k18/14-3-3 ternary complex formulation to promote BRAF/MEK/ERK signal inhibited cell proliferation in hepatocellular carcinoma

被引:6
作者
Yang, Tongwang [1 ,2 ]
Zhu, Cunle [1 ]
Shi, Ying [2 ]
Shen, Yuntai [1 ,2 ]
Gao, Yuxue [2 ]
Zhang, Bowen [3 ]
Jin, Rifeng [4 ]
Liu, Daojie [5 ]
Ouyang, Yabo [2 ]
Liu, Xiaoni [2 ]
Wang, Wenjing [2 ]
Yang, Pengxiang [1 ,2 ]
Xu, Qingguo [1 ]
Cai, Jinzhen [1 ]
Chen, Dexi [1 ,2 ]
机构
[1] Qingdao Univ, Organ Transplantat Ctr, Affiliated Hosp, Qingdao 266003, Peoples R China
[2] Capital Med Univ, Beijing Inst Hepatol, Beijing 100069, Peoples R China
[3] Inner Mongolia Baogang Hosp, Dept Pathol, Baotou 014010, Peoples R China
[4] Carnegie Mellon Univ, Coll Engn, Biomed Engn Dept, Pittsburgh, PA 15213 USA
[5] Haidian Maternal & Child Hlth Hosp, Dept Clin Lab, Beijing 100080, Peoples R China
基金
中国国家自然科学基金;
关键词
PROTEIN; MICE; PHOSPHORYLATION; EXPRESSION; APOPTOSIS; DOMAIN; CYCLE; RAS;
D O I
10.1038/s41417-022-00474-1
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The Apoptosis Stimulating Protein of p53 2 (ASPP2) is a heterozygous insufficient tumor suppressor; however, its molecular mechanism(s) in tumor suppression is not completely understood. ASPP2 plays an essential role in cell growth, as shown by liver hepatocellular carcinoma (LIHC) RNA-seq assay using the Cancer Genome Atlas (TCGA) and High-Throughput-PCR assay using ASPP2 knockdown cells. These observations were further confirmed by in vivo and in vitro experiments. Mechanistically, N-terminus ASPP2 interacted with Keratin 18 (k18) in vivo and in vitro. Interestingly, the RDIVpSGP motif of ASPP2 associates with 14-3-3 and promotes ASPP2/k18/14-3-3 ternary-complex formation which promotes MEK/ERK signal activation by impairing 14-3-3 and BRAF association. Additionally, ASPP2-rAd injection promotes paclitaxel-suppressed tumor growth by suppressing cell proliferation in the BALB/c nude mice model. ASPP2 and k18 were preferentially downregulated in Hepatocellular Carcinoma (HCC), which predicted poor prognosis in HCC patients. Overall, these findings suggested that ASPP2 promoted BRAF/MEK/ERK signal activation by promoting the formation of an ASPP2/k18/14-3-3 ternary complex via the RDIVpSGP motif at the N terminus. Moreover, this study provides novel insights into the molecular mechanism of tumor suppression in HCC patients.
引用
收藏
页码:1616 / 1627
页数:12
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