Mitochondria-targeted catalase induced cell malignant transformation by the downregulation of p53 protein stability via USP28/miR-200b/PP2A-C&#945; axis.

Wen, Chaowei; Huang, Chao; Liao, Xin; Luo, Zhefeng; Huang, Chuanshu

Mitochondria-targeted catalase induced cell malignant transformation by the downregulation of p53 protein stability via USP28/miR-200b/PP2A-Cα axis.

Wen, Chaowei; Huang, Chao; Liao, Xin; Luo, Zhefeng; Huang, Chuanshu.

Afiliación

Wen C; Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325000, Zhejiang, China.
Huang C; Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Liao X; Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Luo Z; Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Huang C; Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, 325000, Zhejiang, China. Electro

Arch Biochem Biophys ; 758: 110047, 2024 Aug.

Article en En | MEDLINE | ID: mdl-38844154

ABSTRACT

ABSTRACT

Antioxidants exert a paradoxical influence on cancer prevention. The latest explanation for this paradox is the different target sites of antioxidants. However, it remains unclear how mitochondria-targeted antioxidants trigger specific p53-dependent pathways in malignant transformation models. Our study revealed that overexpression of mitochondria-targeted catalase (mCAT) instigated such malignant transformation via mouse double minute 2 homolog (MDM2) -mediated p53 degradation. In mouse epithelial JB6 Cl41 cells, the stable expression of mCAT resulted in MDM2-mediated p53 degradation, unlike in catalase-overexpressed Cl41 cells. Further, we demonstrated that mCAT overexpression upregulated ubiquitin-specific protease 28 (USP28) expression, which in turn stabilized c-Jun protein levels. This alteration initiated the activation of the miR-200b promoter transcription activity and a subsequent increase in miR-200b expression. Furthermore, elevated miR-200b levels then promoted its binding to the 3'-untranslated region of protein phosphatase 2A catalytic subunit (PP2A-C) α-isoform mRNA, consequently resulting in PP2A-C protein downregulation. This cascade of events ultimately contributed to increased MDM2 phosphorylation and p53 protein degradation. Thus, the mCAT overexpression triggers MDM2/p53-dependent malignant transformation through USP28/miR-200b/PP2A-Cα pathway, which may provide a new information for understanding mitochondria-targeted antioxidants facilitate the progression to the tumorigenic state.

Asunto(s)

Catalasa; Transformación Celular Neoplásica; Regulación hacia Abajo; MicroARNs; Mitocondrias; Proteína Fosfatasa 2; Estabilidad Proteica; Proteínas Proto-Oncogénicas c-mdm2; Proteína p53 Supresora de Tumor; Ubiquitina Tiolesterasa; Proteína p53 Supresora de Tumor/metabolismo; Proteína p53 Supresora de Tumor/genética; MicroARNs/metabolismo; MicroARNs/genética; Animales; Ratones; Mitocondrias/metabolismo; Proteínas Proto-Oncogénicas c-mdm2/metabolismo; Proteínas Proto-Oncogénicas c-mdm2/genética; Ubiquitina Tiolesterasa/metabolismo; Ubiquitina Tiolesterasa/genética; Transformación Celular Neoplásica/metabolismo; Transformación Celular Neoplásica/genética; Catalasa/metabolismo; Catalasa/genética; Proteína Fosfatasa 2/metabolismo; Proteína Fosfatasa 2/genética; Humanos; Línea Celular; Transducción de Señal; Regulación Neoplásica de la Expresión Génica

Palabras clave

PP2A; USP28; cell transformation; mitochondria-targeted catalase; p53

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Catalasa / Regulación hacia Abajo / Transformación Celular Neoplásica / Proteína p53 Supresora de Tumor / MicroARNs / Ubiquitina Tiolesterasa / Proteínas Proto-Oncogénicas c-mdm2 / Proteína Fosfatasa 2 / Estabilidad Proteica / Mitocondrias Límite: Animals / Humans Idioma: En Revista: Arch Biochem Biophys Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos

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