Mammalian G2 regulatory genes and their possible involvement in genetic instability in cancer cells

Abstract

In the fission yeast Schizosaccharomyces pombe, mitosis is initiated following the activation of the cdc2+/cyclin B kinase. The cdc2+/cyclin B kinase is positively regulated by cdc25+ tyrosine phosphatase and negatively regulated by wee1+/mik1+ tyrosine kinases. This regulatory system is evolutionarily conserved throughout higher eukaryotes. Drosophila and humans contain a cdc25+ gene homolog called String and CDC25Hs (hereafter referred to as CDC25Hul), respectively. We recently cloned a wee1+ homolog (WEE1Hu) and two additional cdc25+ homologs (CDC25Hu2 and CDC25Hu3) from human cells. Consequently, human cells contain at least one wee1+ and three cdc25+ homologs. Both CDC25Hu1 and CDC25Hu2 resemble the cdc25+ gene not only in structure and function but also in the mode of expression. They are expressed mostly in G2. On the other hand, CDC25Hu3 is expressed mostly in early S, indicating that it has some novel function in the early phase of the cell cycle. In all the cell lines examined, CDC25Hu2 is expressed to a greater extent than CDC25Hu1 or CDC25Hu3. The expression of CDC25Hu2 is particularly high in various cancer cells including those transformed by SV40 or human papilloma virus type 16 E6, E7, both of which are well known for their ability to induce genomic instability. In addition, there is a noticeable correlation between the extent of aneuploidy and the level of CDC25Hu2 expression in the cancer cells examined. In view of the fact that overexpression of cdc25+ under certain conditions induces genomic instability in the fission yeast, overexpression of CDC25Hu2 associated with many cancer cells might play at least a role in the induction of their chromosomal abnormalities.