Inactivation of hCDC4 can cause chromosomal instability.
Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century; however, the mechanisms responsible for this abnormality have remained elusive. Here we report the identification of mutations in hCDC4 (also known as Fbw7 or Archipelago) in both human colorectal cancers and their precursor lesions. We show that genetic inactivation of hCDC4, by means of targeted disruption of the gene in karyotypically stable colorectal cancer cells, results in a striking phenotype associated with micronuclei and chromosomal instability. This phenotype can be traced to a defect in the execution of metaphase and subsequent transmission of chromosomes, and is dependent on cyclin E--a protein that is regulated by hCDC4 (refs 2-4). Our data suggest that chromosomal instability is caused by specific genetic alterations in a large fraction of human cancers and can occur before malignant conversion.
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Harith
H
Rajagopalan
Prasad V
PV
Jallepalli
Carlo
C
Rago
Victor E
VE
Velculescu
Kenneth W
KW
Kinzler
Bert
B
Vogelstein
Christoph
C
Lengauer
D000782:Aneuploidy; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D017353:Gene Deletion; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D048629:Micronuclei, Chromosome-Defective / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D012333:RNA, Messenger; D044767:Ubiquitin-Protein Ligases