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  • br Introduction Crm the Chromosome region maintenance protei

    2020-08-05


    Introduction Crm1 (the Chromosome region maintenance 1 protein or Exportin T7 High Yield RNA receptor 1) is a member of the Karyopherin β protein family and the major nuclear export receptor in the cell [1]. It mediates the nuclear export of cargo proteins and certain RNAs from the nucleus into the cytoplasm, across the nuclear pore complex (NPC), and thus facilitates protein and RNA subcellular localisation. Crm1 recognises cargo proteins that carry a nuclear export signal (NES) [2], typically containing three to four critically spaced leucines (LX(1–3)LX(2–3)LXJ, L: leucine, X: spacer, J: leucine, valine or isoleucine) [3], [4]. Such cargo proteins include various transcription factors [5], T7 High Yield RNA receptor proteins [6], [7], and signalling proteins [8], which require timely translocation across the nuclear envelope. Many of the integral processes in the cell thus rely on Crm1 expression and function [9]. Recent studies have reported that the expression of Crm1 is altered in cancer. Crm1 protein levels are elevated in cervical cancer [10], ovarian cancer [11], osteosarcoma [12], glioma [13] and pancreatic cancer [14], with high levels of Crm1 being found to associate with poor patient survival [11], [12], [13], [14]. Moreover, Crm1 expression has been found to be elevated in transformed fibroblasts compared to normal fibroblasts, suggesting that the increased expression of Crm1 is a general feature of the transformed phenotype [10]. The high expression of Crm1 in cancer and transformed cells is functionally relevant, as the inhibition of its expression results in cell death via apoptosis, while inhibition of its expression in normal cells does not [10]. This implicates Crm1 as a potential anti-cancer drug target, and currently studies are underway aiming to develop effective inhibitors of Crm1 [15]. The increased expression of Crm1 protein in cancer derives from increased transcription of Crm1 mRNA [10], suggesting that a transcriptional regulatory mechanism exists for differential Crm1 expression in normal and cancer cells, possibly at the level of promoter control. However, little is known about the factors that regulate the Crm1 promoter. The aim of this study was therefore to investigate Crm1 promoter activity and to identify cis- and trans-elements necessary for high Crm1 expression in cancer cells. We report that NFY/CBP, Sp1 and p53 transcription factors bind the Crm1 promoter and play an important role in Crm1 promoter regulation in cancer and transformed cells.
    Materials and methods
    Results
    Discussion This study is the first to our knowledge that describes upstream cis-elements and transcription factors that are important for Crm1 expression and that drive its high expression in cancer and transformed cells. Using deletion and mutation analysis we identified the −175 to +99 region of the Crm1 promoter as responsible for the differential expression of Crm1 in normal and cancer cells, and identified within this region two CCAAT boxes and a GC box as important regulatory elements. Moreover, we identified binding of NFY/CBP and Sp1 transcription factors to these respective sites in transformed and cancer cells. We propose that the elevated levels of NFY and Sp1 proteins in transformed and cancer cells may be in part responsible for overexpression of Crm1 in these cells. Furthermore, our study is a first to describe a role for p53 in repressing the Crm1 promoter in response to DNA damage; a finding which could also contribute to the high levels of Crm1 in cancer cells, since most cancer cells either contain low levels of p53 protein (through enhanced p53 degradation) or harbour p53 mutations [28].