Inhibition of BUB1 results in genomic instability and anchorage-independent growth of normal human fibroblasts.
The relative contribution of aneuploidy and gene mutations to human tumorigenesis is not yet known. Studies in mice have demonstrated that even single point mutations in oncogenes and tumor suppressor genes can dramatically increase tumor frequency. However, models to evaluate the definitive role of aneuploidy and genomic instability are not yet available. Human fibroblast cells have long been used as a tool for investigating proliferation, senescence, immortalization, and tumorigenesis, all processes that are strongly interrelated. We have now used antisense and ribozyme-mediated temporary inhibition of BUB1 to study the consequences of mitotic checkpoint failure on the development of aneuploidy. The analysis of cell colonies selected by soft agar growth showed evidence of chromosome instability and delayed senescence, without being tumorigenic in nude mice. Our data suggest that chromosomal instability and aneuploidy are early changes that precede tumorigenicity in the multistep process leading to neoplastic transformation.
Musio
Antonio
A
Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Via Fratelli Cervi, 93, 20090 Segrate, Milan, Italy. antonio.musio@itb.cnr.it
Montagna
Cristina
C
Zambroni
Desirée
D
Indino
Esterina
E
Barbieri
Ottavia
O
Citti
Lorenzo
L
Villa
Anna
A
Ried
Thomas
T
Vezzoni
Paolo
P
D000782:Aneuploidy; D051836:COUP Transcription Factors; D002448:Cell Adhesion / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D002675:Child, Preschool; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D002869:Chromosome Aberrations; D004268:DNA-Binding Proteins / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D006801:Humans; D007621:Karyotyping; D008938:Mitosis / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D011987:Receptors, Steroid; D014157:Transcription Factors / Q000235:genetics; D000098550:Structural Maintenance of Chromosome Protein 1
D051836:COUP Transcription Factors; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D016376:Oligonucleotides, Antisense; D047428:Protein Kinase Inhibitors; D011987:Receptors, Steroid; D014157:Transcription Factors; D000098550:Structural Maintenance of Chromosome Protein 1; D011494:Protein Kinases; C584277:BUB1 protein, human; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases