Characterization of an alternatively spliced GADD45 alpha, GADD45 alpha 1 isoform, inarsenic-treated epithelial cells.
Zhang-YD; Beezhold-K; Castranova-V; Shi-XL; Chen-F
Mol Carcinog 2009 May; 48(5):454-464
A new GADD45 alpha isoform, GADD45 alpha 1, was identified in the cellular response to arsenic. DNA sequencing and biochemical analyses suggested that GADD45 alpha 1 is derived from an alternative splicing of the GADD45 alpha mRNA by skipping the region corresponding to exon2 of the gadd45 alpha gene during mRNA maturation. In addition to the Size difference due to the lack of 34 amino acids encoded by exon2, GADD45 alpha 1 and GADD45 alpha proteins differ in their effects on cell proliferation and cell cycle transition. Unlike GADD45 alpha, the GADD45 alpha 1 is unable to attenuate cell growth. In over-expression experiments, the full length GADD45 alpha but not the GADD45 alpha 1, sensitized cells to arsenic-induced prometaphase arrest of the cell cycle. Furthermore, GADD45 alpha 1 appears to be able to antagonize the function of the GADD45 alpha on the G2/M phase cell cycle arrest as demonstrated in cotransfection experiment. Thus, these data suggest that the generation of the GADD45 alpha 1 isoform may not only offset but also antagonize the effects of arsenic and GADD45 alpha, on cell growth and cell cycle regulation.
Biochemical-analysis; Cell-biology; Cell-growth; Cell-metabolism; Cell-transformation; Cellular-function; Cellular-reactions; Chemical-hypersensitivity; Chemical-reactions; Exposure-levels; Exposure-methods; Gene-mutation; Genes;
Author Keywords: GADD45alpha; GADD45alpha1; arsenic; alternative splicing; prometaphase
Fei Chen, The Laboratory of Cancer Signaling and Epigenetics, The Health Effects Laboratory Division, Pathology and Physiology Research Branch, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505