Cancer Cells and Normal Cells Differ in Their Requirements for Thoc1

Abstract

The evolutionarily conserved TREX (Transcription/Export) complex physically couples transcription, messenger ribonucleoprotein particle biogenesis, RNA processing, and RNA export for a subset of genes. HPR1 encodes an essential component of the S. cerevisiae TREX complex. HPR1 loss compromises transcriptional elongation, nuclear RNA export, and genome stability. Yet, HPR1 is not required for yeast viability. Thoc1 is the recently discovered human functional orthologue of HPR1. Thoc1 is expressed at higher levels in breast cancer than in normal epithelia, and expression levels correlate with tumor size and metastatic potential. Depletion of Thoc1 protein (pThoc1) in human cancer cell lines compromises cell proliferation. It is currently unclear whether Thoc1 is essential for all mammalian cells or whether cancer cells may differ from normal cells in their dependence on Thoc1. To address this issue, we have compared the requirements for Thoc1 in the proliferation and survival of isogenic normal and oncogene-transformed cells. Neoplastic cells rapidly lose viability via apoptotic cell death on depletion of pThoc1. Induction of apoptotic cell death is coincident with increased DNA damage as indicated by the appearance of phosphorylated histone H2AX. In contrast, the viability of normal cells is largely unaffected by pThoc1 loss. Normal cells lacking Thoc1 cannot be transformed by forced expression of E1A and Ha-ras, suggesting that Thoc1 may be important for neoplastic transformation. In sum, our data are consistent with the hypothesis that cancer cells require higher levels of pThoc1 for survival than normal cells. If true, pThoc1 may provide a novel molecular target for cancer therapy. [Cancer Res 2007;67(14):6657-64]

Identification of mRNAs that are spliced but not exported to the cytoplasm in the absence of THOC5 in mouse embryo fibroblasts

“…In agreement with these data, THOC1 depletion does not influence the expression of Hsp70 under the non-heat-shock condition in several human cancer cell lines (Li et al 2007). Similarly, it has been discussed in the yeast system that some genes, such as TIR1 (Voynov et al 2006), may require the THO complex upon induction or some environmental stress condition that requires enhanced transcription.…”

“…Similarly, yeast THO-null mutants are slow growers (Chavez et al 2001;Garcia-Rubio et al 2008), and THOC1 and/or THOC2 depletion has a negative effect on growth rate of the Drosophila cell line (Rehwinkel et al 2004). Interestingly, the deletion of THOC1, a major conserved component of the THO complex, causes apoptosis in transformed cells but not in normal fibroblasts (Li et al 2007). The bulk of these data shows that the THO complex plays different roles in distinct cell types.…”

E2f binding-deficientRb1protein suppresses prostate tumor progression in vivo

“…The sequences of quantitative PCR primers and probes are available upon request. Protein was extracted from tissue or cultured cells and analyzed by Western blotting as previously described (40). Blots were stained with primary antibodies against pRb (Pharmingen) or Hsp70 (Stressgen).…”

Nuclear export of mRNA and its regulation by ubiquitylation

“…Thus, abnormal mRNA export and/or altered activities of the mRNA export-associated factors are linked to various diseases such as lethal congenital contracture syndrome, lethal arthrogryposis with anterior horn cell disease, myotonic dystrophy, osteogenesis imperfecta type I, developmental defect and cancers. [1][2][3][4][5][6] To combat these diseases, it is thus crucial to understand the regulatory mechanisms of mRNA export for the development of therapies. In fact, a major progress has been made in last several years towards understanding the nuclear export of mRNA and its coupling to transcription, mRNA processing and post-translational modifications.…”

“…4,5 It is overexpressed in breast cancer cells, and maintains the viability of the cancer cell lines. 2 Thus, Hpr1 can be used as a prognostic marker for cancer cells. Another disease that involves a defect in mRNA export is osteogenesis imperfecta type I.…”