Alternative titles; symbols
HGNC Approved Gene Symbol: CSE1L
Cytogenetic location: 20q13.13 Genomic coordinates (GRCh38): 20:49,046,312-49,096,949 (from NCBI)
Brinkmann et al. (1995) cloned several HeLa cell cDNAs that render MCF-7 breast cancer cells resistant to immunotoxins. Brinkmann et al. (1995) found that one of these cDNAs contains a portion of the human homolog of the yeast chromosome segregation gene CSE1. They noted that an antisense fragment of the human homolog had conferred immunotoxin resistance. They cloned the full-length cDNA for the human homolog and designated it the 'cellular apoptosis susceptibility' (CAS) gene. Northern blot analysis showed that the 3.1-kb CAS mRNA was expressed preferentially in proliferating cells. On Western blots, the predicted 971-amino acid protein migrated as an approximately 100-kD protein; its expression correlated with cell proliferation.
By fluorescence in situ hybridization, Brinkmann et al. (1996) mapped the CAS gene to 20q13. This region had been known to harbor amplifications that correlate with aggressive breast cancer. Brinkmann et al. (1996) used Southern hybridization with a CAS cDNA fragment and fluorescence in situ hybridization with a P1 clone containing the CAS gene and found elevated copy numbers of CAS in a leukemia cell line, 3 of 4 colon cell lines, and 3 of 7 breast cancer cell lines. In 2 of these cell lines (the leukemia and a colon cancer), they attributed elevated CAS copy number to additional copies of chromosome 20.
Brinkmann et al. (1996) noted that CAS may have a dual function in mammalian cells, 1 in apoptosis and another in cell proliferation.
Brinkmann et al. (1996) observed that CAS antisense RNA can interfere with apoptosis mediated by tumor necrosis factor-alpha (191160) and beta (153440) and by ADP-ribosylating toxins, suggesting that CAS may play a role in selected pathways of apoptosis.
Proteins that carry a nuclear localization signal (NLS) are transported into the nucleus by the importin-alpha/-beta heterodimer. Importin-alpha (see 600685 and 600686) binds the NLS, while importin-beta (see 602008) mediates translocation through the nuclear pore complex. After translocation, RanGTP (see RANGAP1; 602362), which has a high predicted concentration in the nucleus and a low predicted concentration in the cytoplasm, binds importin-beta and displaces importin-alpha. Importin-alpha must then be returned to the cytoplasm, leaving the NLS protein behind. Kutay et al. (1997) reported that the CAS protein mediates importin-alpha reexport. CAS binds strongly to importin-alpha only in the presence of RanGTP, forming an importin-alpha/CAS/RanGTP complex. Importin-alpha is released from this complex in the cytoplasm by the combined action of RANBP1 (601180) and RANGAP1. CAS binds preferentially to NLS-free importin-alpha, explaining why import substrates stay in the nucleus. In a 'Minireview,' Ullman et al. (1997) summarized existing research relating to nuclear export receptors.
Brinkmann (1998) provided a review of the role of CAS in proliferation, apoptosis, and cancer.
Crystal Structure
Matsuura and Stewart (2004) presented the 2.0-angstrom crystal structure of the nuclear export complex formed by exportin Cse1p complexed with its cargo Kap60p (importin-alpha; see 600685) and RanGTP (see 602362), thereby providing a structural framework for understanding nuclear protein export and the different functions of RanGTP in export and import. In the complex, Cse1p coils around both RanGTP and Kap60p, stabilizing the RanGTP-state and clamping the Kap60p importin-beta (see 602738)-binding domain, ensuring that only cargo-free Kap60p is exported. By mutagenesis, Matsuura and Stewart (2004) showed that conformational changes in exportins couple cargo binding to high affinity for RanGTP, generating a spring-loaded molecule to facilitate disassembly of the export complex following GTP hydrolysis in the cytoplasm.
Cook et al. (2005) reported the 3.1-angstrom crystal structure of cargo-free eukaryotic Cse1, representing its cytosolic state. Cse1 is compact, consisting of N- and C-terminal arches that interact to form a ring. Comparison with the structure of cargo-bound Cse1 showed a major conformational change leading to opening of the structure upon cargo binding. The largest structural changes occurred within a hinge region centered at HEAT repeat 8. This repeat contains a conserved insertion that connects the RanGTP and importin-alpha contact sites and is essential for cargo binding. In the cargo-free state, the RanGTP-binding sites are occluded and the importin-alpha sites are distorted. Mutations that destabilized the N- and C-terminal interactions uncoupled importin-alpha and Ran binding, suggesting that the closed conformation prevents association of CSE1 with importin-alpha.
Brinkmann, U. CAS, the human homologue of the yeast chromosome-segregation gene CSE1, in proliferation, apoptosis, and cancer. Am. J. Hum. Genet. 62: 509-513, 1998. [PubMed: 9497270] [Full Text: https://doi.org/10.1086/301773]
Brinkmann, U., Brinkmann, E., Gallo, M., Pastan, I. Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1. Proc. Nat. Acad. Sci. 92: 10427-10431, 1995. [PubMed: 7479798] [Full Text: https://doi.org/10.1073/pnas.92.22.10427]
Brinkmann, U., Brinkmann, E., Gallo, M., Scherf, U., Pastan, I. Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis. Biochemistry 35: 6891-6899, 1996. [PubMed: 8639641] [Full Text: https://doi.org/10.1021/bi952829+]
Brinkmann, U., Brinkmann, E., Pastan, I. Expression cloning of cDNAs that render cancer cells resistant to Pseudomonas and diphtheria toxin and immunotoxins. Molec. Med. 1: 206-216, 1995. [PubMed: 8529099]
Brinkmann, U., Gallo, M., Polymeropoulos, M. H., Pastan, I. The human CAS (cellular apoptosis susceptibility) gene mapping on chromosome 20q13 is amplified in BT474 breast cancer cells and part of aberrant chromosomes in breast and colon cancer cell lines. Genome Res. 6: 187-194, 1996. [PubMed: 8963895] [Full Text: https://doi.org/10.1101/gr.6.3.187]
Cook, A., Fernandez, E., Lindner, D., Ebert, J., Schlenstedt, G., Conti, E. The structure of the nuclear export receptor Cse1 in its cytosolic state reveals a closed conformation incompatible with cargo binding. Molec. Cell 18: 355-367, 2005. [PubMed: 15866177] [Full Text: https://doi.org/10.1016/j.molcel.2005.03.021]
Kutay, U., Bischoff, F. R., Kostka, S., Kraft, R., Gorlich, D. Export of importin-alpha from the nucleus is mediated by a specific nuclear transport factor. Cell 90: 1061-1071, 1997. [PubMed: 9323134] [Full Text: https://doi.org/10.1016/s0092-8674(00)80372-4]
Matsuura, Y., Stewart, M. Structural basis for the assembly of a nuclear export complex. Nature 432: 872-877, 2004. [PubMed: 15602554] [Full Text: https://doi.org/10.1038/nature03144]
Ullman, K. S., Powers, M. A., Forbes, D. J. Nuclear export receptors: from importin to exportin. Cell 90: 967-970, 1997. [PubMed: 9323123] [Full Text: https://doi.org/10.1016/s0092-8674(00)80361-x]