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The antagonism between MCT-1 and p53 affects the tumorigenic outcomes
Ravi Kasiappan1, Hung-Ju Shih, Meng-Hsun Wu
1Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.
Background:
MCT-1 oncoprotein accelerates p53 protein degradation via a proteosome pathway. Synergistic promotion of the xenograft tumorigenicity has been demonstrated in circumstance of p53 loss alongside MCT-1 overexpression. However, the molecular regulation between MCT-1 and p53 in tumor development remains ambiguous. We speculate that MCT-1 may counteract p53 through the diverse mechanisms that determine the tumorigenic outcomes.
Results:
MCT-1 has now identified as a novel target gene of p53 transcriptional regulation. MCT-1 promoter region contains the response elements reactive with wild-type p53 but not mutant p53. Functional p53 suppresses MCT-1 promoter activity and MCT-1 mRNA stability. In a negative feedback regulation, constitutively expressed MCT-1 decreases p53 promoter function and p53 mRNA stability. The apoptotic events are also significantly prevented by oncogenic MCT-1 in a p53-dependent or a p53-independent fashion, according to the genotoxic mechanism. Moreover, oncogenic MCT-1 promotes the tumorigenicity in mice xenografts of p53-null and p53-positive lung cancer cells. In support of the tumor growth are irrepressible by p53 reactivation in vivo, the inhibitors of p53 (MDM2, Pirh2, and Cop1) are constantly stimulated by MCT-1 oncoprotein.
Conclusions:
The oppositions between MCT-1 and p53 are firstly confirmed at multistage processes that include transcription control, mRNA metabolism, and protein expression. MCT-1 oncogenicity can overcome p53 function that persistently advances the tumor development.
Insights
The oncogenic MCT-1 protein counteracts the tumor suppressor p53 through multiple regulatory mechanisms, promoting tumor growth and overcoming p53
Area of Science:
- Molecular oncology
- Tumorigenesis research
- Cancer biology
Background:
- MCT-1 oncoprotein accelerates p53 degradation, enhancing xenograft tumorigenicity when p53 is lost.
- The precise molecular interplay between MCT-1 and p53 in tumor development requires elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms by which MCT-1 influences p53 function and tumor development.
- To explore the regulatory relationship between MCT-1 and p53 in cancer.
Main Methods:
- Analysis of MCT-1 promoter activity and mRNA stability in response to wild-type and mutant p53.
- Assessment of apoptotic events and tumor growth in p53-null and p53-positive lung cancer xenografts.
- Evaluation of p53 inhibitors (MDM2, Pirh2, Cop1) expression stimulated by MCT-1.
Main Results:
- MCT-1 is identified as a novel p53 target gene; functional p53 suppresses MCT-1, while MCT-1 negatively feedbacks on p53.
- Oncogenic MCT-1 prevents apoptosis via p53-dependent and independent pathways, promoting tumorigenicity in vivo.
- MCT-1 stimulates p53 inhibitors, rendering tumor growth resistant to p53 reactivation.
Conclusions:
- The study establishes a complex opposition between MCT-1 and p53 across transcriptional control, mRNA metabolism, and protein expression.
- MCT-1 oncogenicity effectively overcomes p53 tumor suppressive functions, driving persistent tumor progression.
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