CHARACTERIZATION OF A HOMEOBOX-RELATED GENE,ATBF1-ITS POTENTIAL ROLE IN CELL GROWTH AND NEURONAL CELL DIFFERENTLATION AND ANALYSIS OF POLYMORPHISMS IN THE TRIPLET REPEAT REGIONS

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I.The ATBF1 gene was originally isolated from a cDNA library derived from human hepatocellular carcinoma cells (Jpn.J.Electrophoresis). Since the alternative splicing mechanisms during cell differentiation and malignant transformaiton were found in a variety of tumor cell lines (J.Mol.Endocrinol.), we tried to isolate the ATBF1 alternative-spliced isoforms. We found a longer ATBF1-cDNA,ATBF1-A,from a cDNA library derived from human fibroblasts. The cDNA of ATBF1-A is 12kb, encoding a 400kDa protein, while the original ATBF1, now termed ATBF1-B,is 8kb encoding a 300kDa protein. ATBF1-A has 4 homeobox and 23 zinc finger domains and one of the largest gene of the homeodomain-zinc finger gene family, and its expression was highly induced during neuronal differentiation (JBC). We also cloned the mouse ATBF1-A,whose expression is high in the developing brain but low in the adult tissues (Gene). On the other hand, the expression of ATBF1-B was specifically induced during granurocytic differen … More tiation of leukemia cells. Taken together, two isoforms of ATBF1 are independently expressed in a cell specific manner, however, further investigation is needed using other cell lineage.Using rabbit polyclonal antibodies, a 250kDa protein was detected by Western bloting that the ATBF1 protein may be cleaved after transcription. Also, a possibility of dimerization of the ATBF1 at the homeodomains were found.II.The expression vectors of ATBF1 were transfected to NIH-3T3 and PC12 cells. The exogenous ATBF1 was detected just after the transfeciton, but lost after several pasages, indicating that its overexpression reduced cell growth whle non-transfectants could survive. These results suggest that the ATBF1 expression may suppress tumor growth through both growth arrest and cellular differentiation.III.There are several triplet repeat regions in the ATBF1 gene, and 6-10 repeat polymorphism was found at a CAA region. DNAs isolated from patients with several neurodegenerative diseases showed no apparent expansion of this region. The ATBF1 was mapped on chromosome 16q22, however, no linkage has been reported in this region so far. When some diseases will be mapped in this region, more study must be conducted. Less