Mutations in the mitotic check point gene, MAD1L1, in human cancers

• Published in: Oncogene Vol. 20; no. 25; pp. 3301 - 3305
• Main Authors: TSUKASAKI, Kunihiro, MILLER, Carl W, GREENSPUN, Erin, ESHAGHIAN, Shervin, KAWABATA, Hiroshi, FUJIMOTO, Takeshi, TOMONAGA, Masao, SAWYERS, Charles, SAID, Jonathan W, KOEFFLER, H. Phillip
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 31.05.2001; Nature Publishing Group
• Subjects: Aneuploidy; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Cancer; Carcinogenesis; Cell culture; Cell physiology; Cell proliferation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - genetics; Codon, Nonsense; Colon; Female; Frameshift Mutation; Fundamental and applied biological sciences. Psychology; Genes; Genomic instability; Glioblastoma; Health sciences; Hematologic Neoplasms - genetics; Hematology; Humans; Leukemia; Lung cancer; Lung Neoplasms - genetics; Lymphoma; MAD1L1 gene; Male; Medicine; Mitosis - genetics; Molecular and cellular biology; Mutants; Mutation; Mutation, Missense; Neoplasm Proteins - genetics; Nocodazole; Osteosarcoma; Osteosarcoma - genetics; Prostate; Prostate cancer; Prostatic Neoplasms - genetics; Tumor cell lines; Tumors; Los Angeles California; United States > US; California; Chromosomal aberration; Human; Regulation(control); Cell line; Mitosis; Cell cycle; Tumor; Aneuploidy; Mutation; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1204421

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.