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. 2015 Jun;18(6):345-50.
doi: 10.3779/j.issn.1009-3419.2015.06.15.

PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer

Yang Wang  1 , Zhidong Xu  2 , Jian-Hua Mao  3 , David Hsieh  2 , Alfred Au  4 , David M Jablons  2 , Hui Li  1 , Liang You  2
Affiliations

PR-Set7 is Degraded in a Conditional Cul4A Transgenic Mouse Model of Lung Cancer

Yang Wang et al. Zhongguo Fei Ai Za Zhi. 2015 Jun.

Abstract

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.

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Figures

1
1
Tumor pathology in Cul4A over-expression mouse lungs. A: Wild-type mouse lungs 8 wk post-infection with Ade-GFP. The surface of the lungs is smooth and uniform. B: Lox-Cul4A mouse lungs 12 wk post-infection with AdenoCre. The surface of the lungs is also smooth and uniform. C: Lox-Cul4A mouse lungs 16 wk post-infection with AdenoCre. The surface of the lungs has a bumpy appearance, arrows indicate the lesions. D: Lox-Cul4A mouse lungs 20 wk post-infection with AdenoCre. An isolated cobblestone-like nodule on the surface of the lungs is visible; the arrow indicates the lesion. E: Lox-Cul4A mouse lungs 24 wk post-infection with AdenoCre. Several nodules on the surface of the lungs have appeared; arrows indicate the lesions. F: Histological sections of wild-type mouse lungs 8 wk post-infection with AdenoCre (HE). G: Histological sections of Lox-Cul4A mouse lungs 12 wk post-infection with AdenoCre; the arrow shows a single lesion (HE). H: Histological sections of Lox-Cul4A mouse lungs 16 wk post-infection with AdenoCre; arrows indicate isolated lesions (HE). I: Histological sections of Lox-Cul4A mouse lungs 20 wk post-infection with AdenoCre; arrow shows a single adenocarcinoma-like lesion (HE). J: Histological sections of Lox-Cul4A mouse lungs 24 wk post-infection with AdenoCre; arrows show diffuse severe adenocarcinoma-like lesions (HE). Scale bar indicates 200 μm.
2
2
Immunostainings of PR-Set 7 in the mouse lung sections at the indicated time. A: 8 wk with Ade-GFP (SP). B: 8 wk with AdenoCre (SP). C: 12 wk with Ade-GFP (SP). D: 12 wk with AdenoCre (SP). E: 16 wk with Ade-GFP (SP). F: 16 wk with AdenoCre (SP).
3
3
Immunostainings of pericentrin and γ-tubulin in mouse lung sections. A: 8 wk with Ade-GFP (SP). B: 8 wk with AdenoCre (SP). C: 12 wk with Ade-GFP (SP). D: 12 wk with AdenoCre (SP). E: 16 wk with Ade-GFP (SP). F: 16 wk with AdenoCre (SP). G: 8 wk with Ade-GFP (SP). H: 8 wk with AdenoCre (SP). I: 12 wk with Ade-GFP (SP). J: 12 wk with AdenoCre (SP). K: 16 wk with Ade-GFP (SP). L: 16 wk with AdenoCre (SP). Scale bar, 100 μm.
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