Mutations in the mitotic check point gene, MAD1L1, in human cancers.
Aneuploidy is a characteristic of the majority of human cancers, and recent studies suggest that defects of mitotic checkpoints play a role in carcinogenesis. MAD1L1 is a checkpoint gene, and its dysfunction is associated with chromosomal instability. Rare mutations of this gene have been reported in colon and lung cancers. We examined a total of 44 cell lines (hematopoietic, prostate, osteosarcoma, breast, glioblastoma and lung) and 133 fresh cancer cells (hematopoietic, prostate, breast and glioblastoma) for alterations of MAD1L1 by RT-PCR-SSCP and nucleotide sequencing. Eight mutations consisting of missense, nonsense and frameshift mutations were found, together with a number of nucleotide polymorphisms. All the alterations in cell lines were heterozygous. Frequency of mutations was relatively high in prostate cancer (2/7 cell lines and 2/33 tumor specimens). We placed a mutant truncated MAD1L1, found in a lymphoma sample, into HOS, Ht161 and SJSA cell lines and found that it was less inhibitory than wild type MAD1L1 at decreasing cell proliferation. Co-expression experiments showed that the mutant form had a dominant-negative effect. Furthermore, this mutant impaired the mitotic checkpoint as shown by decreased mitotic indices in HOS cells expressing mutant MAD1L1 after culture with the microtubule-disrupting agent, nocodazole. Our results suggest a pathogenic role of MAD1L1 mutations in various types of human cancer.
Tsukasaki
K
K
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, CA 90048, USA.
Miller
C W
CW
Greenspun
E
E
Eshaghian
S
S
Kawabata
H
H
Fujimoto
T
T
Tomonaga
M
M
Sawyers
C
C
Said
J W
JW
Koeffler
H P
HP
D001943:Breast Neoplasms / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018389:Codon, Nonsense; D005260:Female; D016368:Frameshift Mutation; D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D008938:Mitosis / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D012516:Osteosarcoma / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics
D018389:Codon, Nonsense; D009363:Neoplasm Proteins