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.
Tongwang YangCunle ZhuYing ShiYuntai ShenYuxue GaoBowen ZhangRifeng JinDaojie LiuYabo OuyangXiaoni LiuWenjing WangPengxiang YangQingguo XuJin-Zhen CaiTongwang YangPublished in: Cancer gene therapy (2022)
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.
Keyphrases
- cell proliferation
- pi k akt
- high throughput
- poor prognosis
- end stage renal disease
- rna seq
- single cell
- cell cycle arrest
- chronic kidney disease
- ejection fraction
- signaling pathway
- newly diagnosed
- peritoneal dialysis
- long non coding rna
- oxidative stress
- prognostic factors
- squamous cell carcinoma
- metabolic syndrome
- cell death
- dna methylation
- early onset
- small molecule
- drug delivery
- reduced graphene oxide
- young adults
- patient reported outcomes
- skeletal muscle
- metastatic colorectal cancer
- dna repair
- lymph node metastasis
- insulin resistance
- amino acid
- squamous cell
- real time pcr