Nuclear export of proteins: The role of nuclear retention

Schmidt-Zachmann, M.S.; Dargemont, Catherine; Kühn, Lukas C.; Nigg, Erich A.

doi:10.1016/0092-8674(93)80051-f

Cited by 225 publications

(160 citation statements)

References 72 publications

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“…Nuclear export is important for function of many nuclear proteins. However, the ability of a protein to leave the nucleus might be determined predominantly by the strength of its interactions with other nuclear components [Schmidt-Zachmann et al, 1993]. Within the nucleus, nuclear proteins can be inhibited from export via masking their nuclear export sequence [Liu et al, 2006] or via interactions with proteins that are themselves retained in the nucleus.…”

Section: Discussionmentioning

confidence: 99%

Nuclear localization of liver X receptor α and β is differentially regulated

Prüfer

Boudreaux

2006

J of Cellular Biochemistry

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Activity of nuclear receptors is regulated by their nuclear localization. Liver X receptors (LXR) a and b are nuclear receptors that regulate transcription of genes for cholesterol metabolism, cholesterol transport, and lipogenesis. While LXR a and b are very similar in structure and exhibit similar ligand binding properties, their physiological roles are quite different. Since the LXRs fall into a class of receptors that move between the nucleus and cytoplasm, experiments were conducted to determine whether LXR a and LXR b show differences in their nuclear localization pattern. To determine the location of each receptor, cell lines stably expressing yellow fluorescent protein (YFP) chimeras with either LXR a or LXR b were examined. Retention in the nucleus of the chimeric proteins in the presence or absence of ligands was assessed using fluorescence microscopy coupled with digitonin permeabilization assays. Surprisingly, differences were found between LXR a and LXR b. Whereas unliganded LXR a was retained in the nucleus, unliganded LXR b was partially exported. Mutations were then introduced into putative nuclear localization sequences (NLS) to determine which sequences are important for nuclear localization and function. Mutation in one such sequence abolished nuclear localization of LXR a, whereas the analogous change in LXR b had a much less dramatic effect. Mutations in analogous putative NLS also differentially affected transcriptional activation by LXR a and LXR b. These data demonstrate for the first time that nuclear retention and localization as well as function of LXR a and LXR b are differentially regulated.

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Section: Discussionmentioning

confidence: 99%

Nuclear localization of liver X receptor α and β is differentially regulated

Prüfer

Boudreaux

2006

J of Cellular Biochemistry

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“…Alternatively, nuclear import could be a default mechanism for proteins lacking a direct import signal sequence. Protein localization will then be determined by the presence or absence of nuclear retention signals (Nakielny and Dreyfuss, 1996;Schmidt-Zachmann et al, 1993;Stauber and Pavlakis, 1998). We are currently investigating in detail if Rex, Rexp21 or cytoplasmic Rev mutants are able to interact with alternative import receptors (e.g., transportin, RanBP5, RanBP7 etc.).…”

Section: Discussionmentioning

confidence: 99%

Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

et al. 1999

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The HTLV-1 Rex protein is an essential shuttle protein required for nuclear export of unspliced and incompletely-spliced viral RNAs. Several trans-dominant (TD) mutant Rex proteins have been reported, however, the mechanism of trans-dominance is not known. We compared TD Rex mutants and found that a natural occurring Rex mutant, Rexp21, lacking the RNA binding domain, was highly TD and inhibited also HIV-1 Rev function. Using fusions to the green uorescent protein (GFP) we observed that Rexp21-GFP displayed a cytoplasmic localization but was actively shuttling between the nucleus and the cytoplasm in live human cells.

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“…Nucleolin is a multifunctional protein that is found in the nucleolus, in the nucleus, in the cytoplasm, and at the cell surface (1,3,5,64,65). A role of nucleolin in activation as well as repression of ribosomal RNA synthesis has been described (1,66).…”

Section: Discussionmentioning

confidence: 99%

Cell Cycle-controlled Interaction of Nucleolin with the Retinoblastoma Protein and Cancerous Cell Transformation

Grinstein

Shan

Karawajew

et al. 2006

Journal of Biological Chemistry

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Retinoblastoma protein (Rb) is a multifunctional tumor suppressor, frequently inactivated in certain types of human cancer. Nucleolin is an abundant multifunctional phosphoprotein of proliferating and cancerous cells, recently identified as cell cycle-regulated transcription activator, controlling expression of human papillomavirus type 18 (HPV18) oncogenes in cervical cancer. Here we find that nucleolin is associated with Rb in intact cells in the G 1 phase of the cell cycle, and the complex formation is mediated by the growth-inhibitory domain of Rb. Association with Rb inhibits the DNA binding function of nucleolin and in consequence the interaction of nucleolin with the HPV18 enhancer, resulting in Rb-mediated repression of the HPV18 oncogenes. The intracellular distribution of nucleolin in epithelial cells is Rb-dependent, and an altered nucleolin localization in human cancerous tissues results from a loss of Rb. Our findings suggest that deregulated nucleolin activity due to a loss of Rb contributes to tumor development in malignant diseases, thus providing further insights into the molecular network for the Rb-mediated tumor suppression.Nucleolin is an abundant multifunctional phosphoprotein of proliferating and cancerous cells (1, 2) (reviewed in Ref.3). High levels of nucleolin expression are related to poor clinical prognosis for certain cancer types (2, 4). A role of nucleolin in activation and repression of gene transcription as well as in regulation of RNA metabolism has been reported (5-7). Nucleolin is a subunit of the transcription factor LR1, which activates expression of the c-myc gene and the EBNA-1 (Epstein-Barr virus nuclear antigen 1) gene in B-cell lymphomas (7-9). Nucleolin is also directly involved in post-transcriptional inhibition of the p53 gene expression (10). As activator of transcription of HPV18 2 oncogenes in cervical cancer cells, nucleolin has oncogenic potential (11). Nucleolin controls the chromatin structure of the HPV18 enhancer in vivo and is directly linked to HPV18-induced cervical cancer formation (11). Nucleolin is a substrate of cyclin-dependent kinases (CDKs), CDK1, CDK4, and CDK2 (12, 13), and its DNA binding activity is most prominent in the S phase of the cell cycle (11). Here we report a functional interaction of nucleolin with Rb, related to cell transformation.Rb is a prototypical tumor suppressor, frequently inactivated in certain types of human cancer, and it controls cell proliferation, differentiation, and survival (14). Therefore, it is important to work out molecular mechanisms of Rb-mediated tumor suppression to understand the cancer disease process (14, 15). Rb functions to constrain cell proliferation by providing a cell cycle checkpoint between the G 1 and S phases (16,17). Phosphorylation of Rb by cyclin-dependent kinases is initiated in mid-G 1 phase, and Rb phosphorylation is associated with G 1 /S transition and S phase progression (18,19). Hypophosphorylated Rb restrains cell proliferation, in part by targeting E2F transcription factors (20 -23)...

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Nuclear export of proteins: The role of nuclear retention

Cited by 225 publications

References 72 publications

Nuclear localization of liver X receptor α and β is differentially regulated

Nuclear localization of liver X receptor α and β is differentially regulated

Titration of cellular export factors, but not heteromultimerization, is the molecular mechanism of trans-dominant HTLV-1 Rex mutants

Cell Cycle-controlled Interaction of Nucleolin with the Retinoblastoma Protein and Cancerous Cell Transformation

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