Novel function of PERP-428 variants impacts lung cancer risk through the differential regulation of PTEN/MDM2/p53-mediated antioxidant activity
| Autor: | Gwo-Tarng Sheu, Ting Jian Wu, Jhong Chio Liou, Jinghua Tsai Chang, Chi Hsiang Wang, Shun-Fa Yang, Huei Lee, Yu-Fan Liu, Han Chang, Shih-Lan Hsu, Chi Ying F. Huang, Chen Yi Liao |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Lung Neoplasms Apoptosis Biochemistry Antioxidants 03 medical and health sciences 0302 clinical medicine Physiology (medical) Genotype Humans Medicine PTEN Genes Tumor Suppressor Lung cancer Gene knockdown Lung biology business.industry Effector PTEN Phosphohydrolase Membrane Proteins Proto-Oncogene Proteins c-mdm2 respiratory system medicine.disease respiratory tract diseases 030104 developmental biology medicine.anatomical_structure biology.protein Cancer research Mdm2 Tumor Suppressor Protein p53 business 030217 neurology & neurosurgery |
| Zdroj: | Free Radical Biology and Medicine. 167:307-320 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2021.02.017 |
| Popis: | Lung cancer is the leading cause of cancer-related deaths worldwide. Identifying genetic risk factors and understanding their mechanisms will help reduce lung cancer incidence. The p53 apoptosis effect is related to PMP-22 (PERP), a tetraspan membrane protein, and an apoptotic effector protein downstream of p53. Although historically considered a tumor suppressor, PERP is highly expressed in lung cancers. Stable knockdown of PERP expression induces CL1-5 and A549 lung cancer cell death, but transient knockdown has no effect. Interestingly, relative to the PERP-428GG genotype, PERP-428CC was associated with the highest lung cancer risk (OR = 5.38; 95% CI = 2.12-13.65, p 0.001), followed by the PERP-428CG genotype (OR = 2.34; 95% CI = 1.55-3.55, p 0.001). Ectopic expression of PERP-428G, but not PERP-428C, protects lung cancer cells against ROS-induced DNA damage. Mechanistically, PERP-428 SNPs differentially regulate p53 protein stability. p53 negatively regulates the expression of the antioxidant enzymes catalase (CAT) and glutathione reductase (GR), thereby modulating redox status. p53 protein stability is higher in PERP-428C-expressing cells than in PERP-428G-expressing cells because MDM2 expression is decreased and p53 Ser20 phosphorylation is enhanced in PERP-428C-expressing cells. The MDM2 mRNA level is decreased in PERP-428C-expressing cells via PTEN-mediated downregulation of the MDM2 constitutive p1 promoter. This study reveals that in individuals with PERP-428CC, CAT/GR expression is decreased via the PTEN/MDM2/p53 pathway. These individuals have an increased lung cancer risk. Preventive antioxidants and avoidance of ROS stressors are recommended to prevent lung cancer or other ROS-related chronic diseases. |
| Databáze: | OpenAIRE |
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