The THO complex (THO) is an evolutionary conserved protein required for the formation of export-competent mRNP. The growing evidence indicates that the metazoan THO plays important roles in cell differentiation and cellular stress response. But the underlying mechanisms are poorly understood. Herein we examined the relevance of THO to cellular signaling pathways involved in cell differentiation and cellular stress response. When we examined the endogenous p53 level in the testis, it was sustained much longer during spermatogenesis in the THO mutant compared to that of wild-type. In flies with impaired THO, overexpression of p53 by eye-specific GAL4 not only enhanced p53-mediated retinal degeneration, but p53 level was also elevated compared to the control flies. Since the body size of the THO mutant flies was significantly larger than control flies, we also examined whether the PI3K/AKT signaling is enhanced in the mutant flies. The results showed that the endogenous level of phosphorylated AKT, which is the active form, was highly elevated in the THO mutants. Taken together our results suggested that both p53 and PI3K/AKT signalings are up-regulated in the flies with impaired THO.