Overexpression of B-type cyclins alters chromosomal segregation.
To identify genes which overexpression results into chromosomal instability (CIN), we developed a biological approach based on a yeast indicator strain in which CIN can be detected by a sectoring phenotype. Screening in this strain of a yeast genomic library cloned into a high copy vector led us to identify, among the clones generating 100% of sectoring colonies, Clb5, one of the six B-type cyclins present in yeast. Overexpression of cyclin B2 and cyclin B1, the two human homologs of Clb5, in the CIN indicator strain resulted also into a sectoring phenotype and induced, like overexpression of Clb5, an abnormal sensitivity to benomyl, indicating that overexpression of B-type cyclins alters the spindle checkpoint. In a series of 38 primary colorectal cancers, we detected in five tumors (13%) an accumulation of cyclin B1, which was neither related to mRNA overexpression nor to mutation within the coding region, and in five other tumors (13%) a 2-10-fold increase of cyclin B2 mRNA which was not related to gene amplification. These results suggest that overexpression of cyclins B, resulting from different mechanisms, could contribute, through an alteration of the spindle checkpoint, to the chromosomal instability observed in cancer.
Sarafan-Vasseur
Nasrin
N
INSERM EMI 9906, Faculté de Médecine et de Pharmacie, IFRMP, 22 boulevard Gambetta, 76183 Rouen Cedex, France.
Lamy
Aude
A
Bourguignon
Jeannette
J
Le Pessot
Florence
F
Hieter
Philip
P
Sesboüé
Richard
R
Bastard
Christian
C
Frébourg
Thierry
T
Flaman
Jean-Michel
JM
D000595:Amino Acid Sequence; D001542:Benomyl / Q000494:pharmacology; D020090:Chromosome Segregation; D015825:Chromosomes, Fungal / Q000378:metabolism*; D019926:Cyclin B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D056744:Cyclin B1; D056765:Cyclin B2; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D008941:Spindle Apparatus / Q000378:metabolism
C534699:CCNB1 protein, human; C503758:CCNB2 protein, human; C076558:CLB5 protein, S cerevisiae; D019926:Cyclin B; D056744:Cyclin B1; D056765:Cyclin B2; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D001542:Benomyl