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GNL3L is a nucleo-cytoplasmic shuttling protein: Role in cell cycle regulation
Indu Jose Thoompumkal, Kumaraswamy Anbarasu, Rehna Krishnan, Sundarasamy Mahalingam
Published in Public Library of Science
2015
PMID: 26274615
Volume: 10
   
Issue: 8
Abstract
GNL3L is an evolutionarily conserved high molecular weight GTP binding nucleolar protein belonging to HSR1-MMR1 subfamily of GTPases. The present investigation reveals that GNL3L is a nucleo-cytoplasmic shuttling protein and its export from the nucleus is sensitive to Leptomycin B. Deletion mutagenesis reveals that the C-terminal domain (amino acids 501-582) is necessary and sufficient for the export of GNL3L from the nucleus and the exchange of hydrophobic residues (M567, L570 and 572) within the C-terminal domain impairs this process. Results from the protein-protein interaction analysis indicate that GNL3L interaction with CRM1 is critical for its export from the nucleus. Ectopic expression of GNL3L leads to lesser accumulation of cells in the 'G2/M' phase of cell cycle whereas depletion of endogenous GNL3L results in 'G2/M' arrest. Interestingly, cell cycle analysis followed by BrdU labeling assay indicates that significantly increased DNA synthesis occurs in cells expressing nuclear export defective mutant (GNL3LΔNES) compared to the wild type or nuclear import defective GNL3L. Furthermore, increased hyperphosphorylation of Rb at Serine 780 and the upregulation of E2F1, cyclins A2 and E1 upon ectopic expression of GNL3LΔNES results in faster 'S' phase progression. Collectively, the present study provides evidence that GNL3L is exported from the nucleus in CRM1 dependent manner and the nuclear localization of GNL3L is important to promote 'S' phase progression during cell proliferation. © 2015 Thoompumkal et al.
About the journal
JournalPLoS ONE
PublisherPublic Library of Science
ISSN19326203
Open AccessYes
Concepts (69)
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    CYCLIN A2
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    Cyclin e
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    CYCLIN E1
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    EXPORTIN 1
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    GUANINE NUCLEOTIDE BINDING PROTEIN
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    GUANINE NUCLEOTIDE BINDING PROTEIN LIKE 3 LIKE PROTEIN
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    LEPTOMYCIN B
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    Retinoblastoma protein
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    TRANSCRIPTION FACTOR E2F1
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    Unclassified drug
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    CCNA2 PROTEIN, HUMAN
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    CCNE1 PROTEIN, HUMAN
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    CYCLIN A2
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    E2F1 PROTEIN, HUMAN
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    GNL3L PROTEIN, HUMAN
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    GUANINE NUCLEOTIDE BINDING PROTEIN
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    Nuclear protein
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    ONCOPROTEIN
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    TRANSCRIPTION FACTOR E2F1
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    Article
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    Carboxy terminal sequence
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    Cell cycle g2 phase
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    CELL CYCLE REGULATION
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    Cell cycle s phase
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    Cell nucleus
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    Cell proliferation
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    Cellular distribution
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    Controlled study
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    Dna synthesis
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    Human
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    Human cell
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    Nucleocytoplasmic transport
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    Protein phosphorylation
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    Protein protein interaction
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    Upregulation
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    3t3 cell line
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    ACTIVE TRANSPORT
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    Cell division
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    CHLOROCEBUS AETHIOPS
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    COS CELL LINE
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    Genetics
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    Hela cell line
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    Mutagenesis
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    Physiology
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    ACTIVE TRANSPORT, CELL NUCLEUS
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    Animals
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    CERCOPITHECUS AETHIOPS
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    COS CELLS
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    CYCLIN A2
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    E2F1 TRANSCRIPTION FACTOR
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    G2 PHASE
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    GTP-BINDING PROTEINS
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    Hek293 cells
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    Hela cells
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    Hep g2 cells
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    Humans
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    Mcf-7 cells
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    Mice
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    Nih 3t3 cells
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    Nuclear proteins
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    ONCOGENE PROTEINS
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    UP-REGULATION