STRUCTURAL AND FUNCTIONAL ANALYSIS OF A NEW CANDIDATE TUMOR-SUPPRESSOR GENE,DAN

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(1) Characterization of the human DAN geneThe human genomic DNA,which contains the entire region of DAN gene, has been cloned from the standard phage- and the P1-based genomic libraries and its nucleotide sequence was determined. The human DAN gene is composed of four exons and there exist the possible CA-repeats within the first intron. Importantly, allelic loss of DAN gene locs was observed in three neuroblastoma tissues with N-myc gene amplification. At present, the molecular basis of the structural abnormalities of DAN gene in some of the neuroblastomas is not known.(2) ldentification of a new cellular protein which can associate with DANBy using a yeast two-hybrid screening, a new cellular protein (DA41) which can interact with DAN was identified. The DA41 cDNA encodes a new protein compised of 582 amino acids. The expression of DA41 gene was regulated in a cell cycle-dependent manner, raising a possibility that DA41 might possess a cell cycle-reglatory role. When DA41 gene was overexpressed in ras-transformed 3Y1 cells, phenotypic reversion was observed.Interestingly, the amount of WAF1 was increased and the activity of CDK2 was significantly reduced in these DA41-overexpressing cells. These results strongly suggest that the DAN-DA41 complex could contain a significant role in a cell cycle regulation.