Document Detail


The ubiquitin ligase APC(Cdh1) is required to maintain genome integrity in primary human cells.
MedLine Citation:
PMID:  17700535     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ensuring precise DNA replication and chromosome segregation is essential during cell division in order to provide genomic stability and avoid malignant growth. Proteolytic control of cell cycle regulators by the anaphase-promoting complex, activated by Cdh1 (APC(Cdh1)), is responsible for a stable G1 phase after mitotic exit allowing accurate preparation for DNA replication in the following S phase. APC(Cdh1) target proteins are frequently upregulated in tumor cells and the inactivation of human Cdh1 might interfere with genome integrity by target stabilization. Here we show that APC(Cdh1) is required for maintaining genomic integrity in primary human cells. Lentiviral-delivered strong and stable suppression of Cdh1 by RNA interference (RNAi) causes aberrant accumulation of several APC(Cdh1) target proteins, such as cyclin A, B, Aurora A or Plk1, which control accurate and equal distribution of the genetic information to daughter cells. This induces a premature and prolonged S phase, mitotic-entry delay and defects in chromosome separation and cytokinesis. Cell cycle deregulation by stable knockdown of Cdh1 leads to activation of p53/p21 and genomic instability, which is further increased by codepletion of p53. Thus, stabilization of APC(Cdh1) targets may initiate aberrant DNA replication and chromosome separation, and trigger a p53 response by deregulating G1 in primary human cells.
Authors:
D Engelbert; D Schnerch; A Baumgarten; R Wäsch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2007-08-13
Journal Detail:
Title:  Oncogene     Volume:  27     ISSN:  1476-5594     ISO Abbreviation:  Oncogene     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-07     Completed Date:  2008-03-04     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  England    
Other Details:
Languages:  eng     Pagination:  907-17     Citation Subset:  IM    
Affiliation:
Department of Hematology and Oncology, Albert-Ludwigs University Medical Center, Freiburg, Germany.
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MeSH Terms
Descriptor/Qualifier:
Blotting, Western
Bone Neoplasms / genetics*,  metabolism,  pathology
Cell Cycle Proteins / genetics,  metabolism
Cell Proliferation
Cells, Cultured
Cyclin A / genetics,  metabolism
Cyclin B / genetics,  metabolism
Cyclin-Dependent Kinase Inhibitor p21
Fibroblasts / metabolism,  pathology
Flow Cytometry
Fluorescent Antibody Technique
G1 Phase / physiology
Genomic Instability / physiology*
Humans
Kidney / metabolism,  pathology
Lentivirus / genetics
Mitosis / physiology
Osteosarcoma / genetics*,  metabolism,  pathology
Protein-Serine-Threonine Kinases / genetics,  metabolism
Proto-Oncogene Proteins / genetics,  metabolism
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / pharmacology
Reverse Transcriptase Polymerase Chain Reaction
S Phase / physiology
Tumor Suppressor Protein p53
Ubiquitin / metabolism
Ubiquitin-Protein Ligase Complexes / antagonists & inhibitors,  genetics,  physiology*
Ubiquitin-Protein Ligases / metabolism*
Chemical
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cell Cycle Proteins; 0/Cyclin A; 0/Cyclin B; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/TP53 protein, human; 0/Tumor Suppressor Protein p53; 0/Ubiquitin; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/aurora kinase; EC 2.7.11.1/polo-like kinase 1; EC 6.3.2.19/Ubiquitin-Protein Ligase Complexes; EC 6.3.2.19/Ubiquitin-Protein Ligases; EC 6.3.2.19/anaphase-promoting complex

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