p53 and PI3K/AKT Signalings Are Up-Regulated in Flies with Defects in the THO Complex

Abstract

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. INTRODUCTIONThe eukaryotic gene expression requires complex regulation at various stages. The THO complex (THO) participates in the eukaryotic gene expression at the interface between transcription and RNA export. THO was first discovered as a protein complex that connects transcription elongation with mitotic recombination in budding yeast (Chávez et al., 2000). Subsequent studies have revealed that THO is involved in forming an optimal mRNP for nuclear export, preventing the nascent RNA from interacting with the DNA template (Jimeno et al., 2002). Metazoans also have a functional homolog of THO, although their subunit composition is slightly different from that of budding yeast (Masuda et al., 2005;Rehwinkel et al., 2004). Metazoan THO consists of 5 subunits, THOC1/HPR1, THOC2/ THO2, THOC5, THOC6 and THOC7. Now, it is clear that THO is required for the biogenesis of export-competent mRNPs at the single cell level (review by Jimeno and Aguilera, 2010).However, our understanding of THO function at the multicellular organism level is very limited. Several lines of recent evidence have suggested that metazoan THO has cell type-specific roles during development (Griaud et al., 2012;Kopytova et al., 2010;Mancini et al., 2010;Moon et al., 2011;Wang et al., 2009). In mice homozygous for a hyphomorphic Thoc1 allele, spermatogenesis was severely compromised due to defects in the expression of genes required for normal cell differentiation in the testis, while most other tissues appeared to be unaffected (Wang et al., 2009). Using conditional knock-out mice, Mancini et al. (2010) showed that THOC5 was an essential element in the maintenance of hematopoiesis, whereas it was less important in differentiated cell types such as hepatocytes and heart muscles. In addition, it has been shown that THOC1 was differentially expressed in human cancers; i...

Identification of an individualized RNA binding protein‐based prognostic signature for diffuse large B‐cell lymphoma

“…Among the identified six RBP, THOC5, SNIP1, PSIP1, and ZCCHC7 were served as translation regulators. THOC5 is involved in the regulation of transcription factor expression and the processing and transport of mRNA, which has an important role in hematopoietic stem cells for survival 14‐17 . THOC5 couples macrophage colony‐stimulating factor receptor signaling and contributes to macrophage and monocyte differentiation, suggesting the potential roles in the development of lymphoma 18‐20 .…”