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Published on: August 19, 2014
The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability
Etna Abad1, Jérémy Sandoz1, Gerard Romero1,2
1Department of Medicine and Life Sciences, Universidad Pompeu Fabra, Barcelona, 08003, Spain.
Background:
TP53, the most frequently mutated gene in human cancers, orchestrates a complex transcriptional program crucial for cancer prevention. While certain TP53-dependent genes have been extensively studied, others, like the recently identified RNF144B, remained poorly understood. This E3 ubiquitin ligase has shown potent tumor suppressor activity in murine Eμ Myc-driven lymphoma, emphasizing its significance in the TP53 network. However, little is known about its targets and its role in cancer development, requiring further exploration. In this work, we investigate RNF144B's impact on tumor suppression beyond the hematopoietic compartment in human cancers.
Methods:
Employing TP53 wild-type cells, we generated models lacking RNF144B in both non-transformed and cancerous cells of human and mouse origin. By using proteomics, transcriptomics, and functional analysis, we assessed RNF144B's impact in cellular proliferation and transformation. Through in vitro and in vivo experiments, we explored proliferation, DNA repair, cell cycle control, mitotic progression, and treatment resistance. Findings were contrasted with clinical datasets and bioinformatics analysis.
Results:
Our research underscores RNF144B's pivotal role as a tumor suppressor, particularly in lung adenocarcinoma. In both human and mouse oncogene-expressing cells, RNF144B deficiency heightened cellular proliferation and transformation. Proteomic and transcriptomic analysis revealed RNF144B's novel function in mediating protein degradation associated with cell cycle progression, DNA damage response and genomic stability. RNF144B deficiency induced chromosomal instability, mitotic defects, and correlated with elevated aneuploidy and worse prognosis in human tumors. Furthermore, RNF144B-deficient lung adenocarcinoma cells exhibited resistance to cell cycle inhibitors that induce chromosomal instability.
Conclusions:
Supported by clinical data, our study suggests that RNF144B plays a pivotal role in maintaining genomic stability during tumor suppression.
Insights
RNF144B acts as a tumor suppressor by maintaining genomic stability. Its deficiency promotes cancer cell proliferation and treatment resistance, highlighting its importance in cancer prevention.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- TP53 is a critical tumor suppressor gene frequently mutated in human cancers.
- RNF144B, an E3 ubiquitin ligase, has demonstrated tumor suppressor activity but its precise role and targets remain largely unknown.
- This study investigates RNF144B's function in human cancers beyond the hematopoietic system.
Purpose of the Study:
- To elucidate the tumor suppressive role of RNF144B in human cancers.
- To identify RNF144B's molecular targets and mechanisms of action.
- To assess the clinical relevance of RNF144B in cancer development and patient prognosis.
Main Methods:
- Generated RNF144B-deficient cell models (human and mouse, normal and cancerous).
- Utilized proteomics, transcriptomics, in vitro/in vivo functional assays (proliferation, DNA repair, cell cycle, mitosis).
- Analyzed clinical datasets and performed bioinformatics analysis.
Main Results:
- RNF144B deficiency enhances cellular proliferation and transformation, particularly in lung adenocarcinoma.
- RNF144B regulates protein degradation involved in cell cycle, DNA damage response, and genomic stability.
- RNF144B loss correlates with chromosomal instability, mitotic defects, aneuploidy, and poor prognosis in human tumors.
- RNF144B-deficient lung cancer cells show resistance to specific chemotherapies.
Conclusions:
- RNF144B is a crucial tumor suppressor that maintains genomic stability.
- RNF144B's function is vital for preventing cancer development and progression.
- Clinical data supports RNF144B's role in tumor suppression and patient outcomes.
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