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

Abstract

Background and objectiveMaintenance 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 afer DNA damage. Tis might occur to ensure appropriate changes in chromosome structure during the cell cycle or to preserve genome integrity afer DNA damage.MethodsWe 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 frst 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 identifed higher protein level changes of γ-tubulin and pericentrin by IHC.ResultsTe level of PR-Set7 down-regulated in the preneoplastic and adenocarcinomous lesions following over-expression of Cul4A. We also identifed higher levels of the proteins pericentrin and γ-tubulin in Cul4A mouse lungs induced by AdenoCre.ConclusionPR-Set7 is a direct target of Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.