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Title: PR-Set7 is degraded in a conditional Cul4A transgenic mouse model of lung cancer

Background and objective. 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. Conclusion. PR-Set7 is a direct target ofmore » Cul4A for degradation and involved in the formation of lung tumors in the conditional Cul4A transgenic mouse model.« less
Authors:
 [1] ;  [2] ;  [3] ;  [2] ;  [4] ;  [2] ;  [1] ;  [2]
  1. Capital University of Medical Science, Beijing (China). Thoracic Surgery Dept.
  2. Univ. of California, San Francisco, CA (United States). Thoracic Oncology Lab.
  3. Lawrence Berkeley National Lab., CA (United States). Life Sciences Div.
  4. Univ. of California, San Francisco, CA (United States). Div. of Diagnostic Pathology
Publication Date:
OSTI Identifier:
1212155
Grant/Contract Number:
AC02-05CH11231
Type:
Accepted Manuscript
Journal Name:
Chinese Journal of Lung Cancer
Additional Journal Information:
Journal Volume: 18; Journal Issue: 6; Journal ID: ISSN 1009-3419
Publisher:
China Association for Science and Technology
Research Org:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES lung neoplasms; Cul4A; AdenoCre; mouse model; PR-Set7; γ-tubulin; pericentrin; cell cycle