Characterization of an alternatively spliced GADD45alpha, GADD45alpha1 isoform, in arsenic-treated epithelial cells.

A new GADD45alpha isoform, GADD45alpha1, was identified in the cellular response to arsenic. DNA sequencing and biochemical analyses suggested that GADD45alpha1 is derived from an alternative splicing of the GADD45alpha mRNA by skipping the region corresponding to exon2 of the gadd45alpha gene during mRNA maturation. In addition to the size difference due to the lack of 34 amino acids encoded by exon2, GADD45alpha1 and GADD45alpha proteins differ in their effects on cell proliferation and cell cycle transition. Unlike GADD45alpha, the GADD45alpha1 is unable to attenuate cell growth. In over-expression experiments, the full length GADD45alpha, but not the GADD45alpha1, sensitized cells to arsenic-induced prometaphase arrest of the cell cycle. Furthermore, GADD45alpha1 appears to be able to antagonize the function of the GADD45alpha on the G2/M phase cell cycle arrest as demonstrated in cotransfection experiment. Thus, these data suggest that the generation of the GADD45alpha1 isoform may not only offset but also antagonize the effects of arsenic and GADD45alpha on cell growth and cell cycle regulation.