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Isolation of Murine and Human Homologues of the Fission-Yeast dis3⁺ Gene Encoding a Mitotic-Control Protein and Its Overexpression in Cancer Cells with Progressive Phenotype¹

Laboratory of Molecular Medicine, Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108 [J. L., T. K., K. O., H. K., Y. N.]; Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo 170 [T. Y.]; Laboratory of Biomedical Research, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113 [T. T.]; Department of Surgery, The Center for Adult Disease, Osaka 537 [S. N., S. I.]; First Department of Surgery, Tokyo Medical and Dental University, Tokyo 113 [J. L., M. E.], Japan

To investigate genes involved in metastasis, we used a differential display method to compare the levels of gene expression in three cell lines derived from murine colon-adenocarcinoma 26 that show different metastatic potentials. The results, and subsequent Northern analyses, confirmed that one gene was expressed most strongly in NL17, the cell line with the highest experimentally metastatic potential to the lung; strongly in NL22, the line with moderately metastatic potential; and very weakly in NL4, which has no metastatic potential in recipient mice. Using this fragment as a probe, we isolated the murine cDNA as well as its human homologue and determined their DNA sequences. The cDNA sequences from both species contained open reading frames of 2874 nucleotides, encoding peptides of 958 amino acids with calculated molecular weights of approximately 109,000; the murine and human nucleotide sequences were 90% identical. The deduced amino acid sequences of these cDNAs revealed significant homology (45% identity) to the dis3⁺ gene product of Schizosaccharomyces pombe, a protein thought to be essential for mitotic control in the yeast. We therefore termed the murine and human genes hmc (homologue to the mitotic-control gene) and HMC, respectively. In 7 of 13 patients with colorectal cancers and liver metastases, expression of HMC was increased up to 38-fold in primary tumors and metastatic foci as compared to adjacent normal colorectal mucosa. An increase in expression of HMC, its novel product likely to belong to a structurally distinct family of mitotic-control proteins, may be associated with malignant phenotypes of some colorectal cancers.

¹ This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.

² To whom requests for reprints should be addressed. Phone: 81-35449-5372; Fax: 81-35449-5433.

Received 9/30/96. Accepted 1/ 6/97.

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