Overexpression of the anaphase promoting complex/cyclosome inhibitor Emi1 leads to tetraploidy and genomic instability of p53-deficient cells.
The anaphase promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase that controls the cell cycle by directing the ubiquitin-dependent proteolysis of S-phase and mitosis promoting factors. Emi1 is an E2F transcriptional target that drives cell cycle progression from G1/S through early mitosis by inhibiting the APC/C's ubiquitin ligase activity, and thus facilitates accumulation of APC/C substrates. Using cell culture model systems, we found that Emi1 overexpression leads to proliferation, tetraploidy and genome instability of cells deficient for p53. We propose that loss of pRb repression of E2F-mediated transcription causing misregulation of Emi1 and APC/C substrates results in the generation of tetraploidy and proliferation of genomically unstable cells in the absence of normal p53 function. This represents a potentially important mechanism by which pRb and p53 dysfunction may contribute to tumorigenesis through the generation of genomic instability.
Lehman
Norman L
NL
Department of Pathology, Stanford University, Stanford, California 94305, USA. nlehman@stanford.edu
Verschuren
Emmy W
EW
Hsu
Jerry Y
JY
Cherry
Athena M
AM
Jackson
Peter K
PK
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D049109:Cell Proliferation; D044783:F-Box Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D042822:Genomic Instability; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000209:etiology; D011123:Polyploidy; D011506:Proteins / Q000235:genetics; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018797:Cell Cycle Proteins; C498959:Emi1 protein, mouse; D044783:F-Box Proteins; C498960:FBXO5 protein, human; D011506:Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044767:Ubiquitin-Protein Ligases