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PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer
Yang Wang1, Zhidong Xu2, Jian-Hua Mao3
1Thoracic Surgery Department, Beijing Chao-Yang Hospital, Capital University of Medical Science, Beijing 100020, China.
Background:
Maintenance of genomic integrity is essential to ensure normal organismal development and to prevent diseases such as cancer. PR-Set7 (also known as Set8) is a cell cycle regulated enzyme that catalyses monomethylation of histone 4 at Lys20 (H4K20me1) to promote chromosome condensation and prevent DNA damage. Recent studies show that CRL4CDT2-mediated ubiquitylation of PR-Set7 leads to its degradation during S phase and after DNA damage. This might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity after DNA damage.
Methods:
We developed a new model of lung tumor development in mice harboring a conditionally expressed allele of Cul4A. We have therefore used a mouse model to demonstrate for the first time that Cul4A is oncogenic in vivo. With this model, staining of PR-Set7 in the preneoplastic and tumor lesions in AdenoCre-induced mouse lungs was performed. Meanwhile we identified higher protein level changes of γ-tubulin and pericentrin by IHC.
Results:
The level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identified higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre.
Conclusions:
PR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.
Insights
Cul4A promotes lung tumor development by targeting PR-Set7 for degradation, impacting genomic integrity. This study demonstrates Cul4A
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Genomic integrity is crucial for development and preventing diseases like cancer.
- PR-Set7 (Set8) regulates H4K20me1 for chromosome condensation and DNA damage prevention.
- CRL4CDT2 targets PR-Set7 for degradation during S phase and after DNA damage.
Purpose of the Study:
- To investigate the role of Cul4A in lung tumor development in vivo.
- To determine if Cul4A affects PR-Set7 levels during lung tumorigenesis.
- To explore the relationship between Cul4A, PR-Set7, and lung cancer formation.
Main Methods:
- Development of a novel mouse model for lung tumor development with a conditional Cul4A allele.
- Analysis of PR-Set7 protein levels in preneoplastic and tumor lesions in AdenoCre-induced mouse lungs.
- Immunohistochemical (IHC) analysis of γ-tubulin and pericentrin protein levels.
Main Results:
- Cul4A was found to be oncogenic in vivo.
- PR-Set7 levels were downregulated in preneoplastic and adenocarcinomatous lesions with Cul4A overexpression.
- Increased levels of pericentrin and γ-tubulin were observed in Cul4A-expressing mouse lungs.
Conclusions:
- PR-Set7 is a direct degradation target of Cul4A.
- Cul4A plays a role in lung tumor formation within this conditional transgenic mouse model.
- The Cul4A-PR-Set7 axis is implicated in lung tumorigenesis.
