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  • LY294002 br Nuclear export and the functions of CRM


    Nuclear export and the functions of CRM1 The nuclear envelope provides a compartmentalized intracellular environment for DNA replication, the synthesis of RNA, and production of ribosomes, and, as such, it can regulate cellular biological processes including apoptosis and proliferation. Nucleocytoplasmic trafficking of RNAs, ribosomes, regulators of transcription, and cell cycle modulators is tightly regulated by the nuclear pore complex, and by the presence of transport receptor molecules including the karyopherin-β family proteins (Turner et al., 2012). Each karyopherin-β protein recognizes a unique group of cargo proteins or RNAs, and conveys their nucleocytoplasmic import or export. The presence of either a nuclear localization signal/nuclear export signal (NES) amino LY294002 sequence facilitates cargo molecule recognition by the transporter. CRM1 is among seven exportins, and the only one that mediates the transport of over 230 proteins including tumor suppressors (e.g., p53, p73, and FOXO1), growth regulator/pro-inflammatory (e.g., IkB, Rb, p21, p27, BRCA1, and APC), and anti-apoptotic proteins (e.g., NPM and AP-1) (Table 1, the aforementioned proteins are part of a comprehensive list appearing on the web page: (Kau et al., 2004, Turner et al., 2012, Xu et al., 2012). CRM1 is also required for the transport of several mRNAs, proteins, and rRNAs that are essential for ribosomal biogenesis (Thomas and Kutay, 2003, Golomb et al., 2012, Bai et al., 2013, Tabe et al., 2013). The CRM1 protein is encoded by the XPO1 gene and was originally identified by a genetic screen of S. pombe that revealed involvement of the protein in control of chromosomal structure (Adachi & Yanagida, 1989). CRM1 was later characterized and designated as a ubiquitous nuclear export receptor protein of the karyopherin-β family, which exports the cargo proteins harboring a specific NES into the cytoplasm (Fornerod et al., 1997, Fukuda et al., 1997, Ossareh-Nazari et al., 1997). CRM1 is upregulated in a variety of solid tumor types (e.g., osteosarcomas, gliomas, and pancreatic, ovarian, cervical, and renal carcinomas) (Noske et al., 2008, Huang et al., 2009, Shen et al., 2009, van der Watt et al., 2009, Yao et al., 2009, Inoue et al., 2013), as well as in hematological malignancies (e.g., acute myeloid/lymphoid leukemia (AML/ALL), chronic myeloid/lymphoid leukemia (CML/CLL), mantle cell lymphomas (MCL), and multiple myeloma [MM]) (Sakakibara et al., 2011, Lapalombella et al., 2012, Ranganathan et al., 2012, Etchin et al., 2013a, Etchin et al., 2013b, Kojima et al., 2013, Schmidt et al., 2013, Walker et al., 2013, Zhang et al., 2013, Tai et al., 2014, Yoshimura et al., 2014). In fact, the overexpression of CRM1 is positively correlated with poor prognosis in these malignancies (Noske et al., 2008, Huang et al., 2009, Shen et al., 2009, Yao et al., 2009, Kojima et al., 2013, Tai et al., 2014, Yoshimura et al., 2014). Therefore, it has been suggested that alterations in nucleocytoplasmic trafficking, and hence the aberrant cytoplasmic localization of tumor suppressor proteins, cell cycle regulators, and/or pro-apoptotic proteins, as well as the deregulation of ribosomal biogenesis, is associated with oncogenesis and resistance to chemotherapy. For CRM1-substrate binding to occur, the cargo molecule must have a leucine-rich NES (Wen et al., 1995, Fukuda et al., 1997). The NES for CRM1 contains hydrophobic amino acids, including isoleucine, leucine, methionine, phenylalanine, and valine (Kutay & Guttinger, 2005). A consensus motif for this NES is comprised of 10 to 15 amino acid residues containing several spaced hydrophobic amino acids. These can be ordered as HX2-3HX2-3HXH. In this designation, H is a hydrophobic amino acid (i.e., isoleucine, leucine, methionine, phenylalanine, or valine), X is any amino acid, and the subscripts indicate the potential number of repeats (Turner et al., 2012). Together, these amino acids form an alpha-helix-loop and/or all loop structure that can bind the hydrophobic groove of CRM1 (Dong et al., 2009a, Dong et al., 2009b).