Nuclear accumulation of cyclin D1 during S phase inhibits Cul4-dependent Cdt1 proteolysis and triggers p53-dependent DNA rereplication.
Deregulation of cyclin D1 occurs in numerous human cancers through mutations, alternative splicing, and gene amplification. Although cancer-derived cyclin D1 mutants are potent oncogenes in vitro and in vivo, the mechanisms whereby they contribute to neoplasia are poorly understood. We now provide evidence derived from both mouse models and human cancer-derived cells revealing that nuclear accumulation of catalytically active mutant cyclin D1/CDK4 complexes triggers DNA rereplication, resulting from Cdt1 stabilization, which in turn triggers the DNA damage checkpoint and p53-dependent apoptosis. Loss of p53 through mutations or targeted deletion results in increased genomic instability and neoplastic growth. Collectively, the data presented reveal mechanistic insights into how uncoupling of critical cell cycle regulatory events will perturb DNA replication fidelity, thereby contributing to neoplastic transformation.
Aggarwal
Priya
P
The Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Lessie
Matthew D
MD
Lin
Douglas I
DI
Pontano
Laura
L
Gladden
Andrew B
AB
Nuskey
Beth
B
Goradia
Ami
A
Wasik
Mariusz A
MA
Klein-Szanto
Andres J P
AJ
Rustgi
Anil K
AK
Bassing
Craig H
CH
Diehl
J Alan
JA
D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D041681:NIH 3T3 Cells; D012516:Osteosarcoma / Q000473:pathology; D016196:S Phase; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C467199:CDT1 protein, human; C114234:CUL4A protein, human; C517832:CUL4B protein, human; D018797:Cell Cycle Proteins; C524851:Cul4B protein, mouse; C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D008070:Lipopolysaccharides; C498645:Ris2 protein, mouse; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D004247:DNA