Document Detail

Nuclear-to-cytoplasmic relocalization of the proliferating cell nuclear antigen (PCNA) during differentiation involves a chromosome region maintenance 1 (CRM1)-dependent export and is a prerequisite for PCNA antiapoptotic activity in mature neutrophils.
MedLine Citation:
PMID:  22846997     Owner:  NLM     Status:  MEDLINE    
Neutrophils are deprived of proliferative capacity and have a tightly controlled lifespan to avoid their persistence at the site of injury. We have recently described that the proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repair of proliferating cells, is a key regulator of neutrophil survival. In neutrophils, PCNA was localized exclusively in the cytoplasm due to its nuclear-to-cytoplasmic relocalization during granulocytic differentiation. We showed here that leptomycin B, an inhibitor of the chromosome region maintenance 1 (CRM1) exportin, inhibited PCNA relocalization during granulocytic differentiation of HL-60 and NB4 promyelocytic cell lines and of human CD34(+) primary cells. Using enhanced green fluorescent protein fusion constructs, we have demonstrated that PCNA relocalization involved a nuclear export signal (NES) located from Ile-11 to Ile-23 in the PCNA sequence. However, this NES, located at the inner face of the PCNA trimer, was not functional in wild-type PCNA, but instead, was fully active and leptomycin B-sensitive in the monomeric PCNAY114A mutant. To test whether a defect in PCNA cytoplasmic relocalization would affect its antiapoptotic activity in mature neutrophils, a chimeric PCNA fused with the SV40 nuclear localization sequence (NLS) was generated to preclude its cytoplasmic localization. As expected, neutrophil-differentiated PLB985 cells expressing ectopic SV40NLS-PCNA had an increased nuclear PCNA as compared with cells expressing wild-type PCNA. Accordingly, the nuclear PCNA mutant did not show any antiapoptotic activity as compared with wild-type PCNA. Nuclear-to-cytoplasmic relocalization that occurred during myeloid differentiation is essential for PCNA antiapoptotic activity in mature neutrophils and is dependent on the newly identified monomerization-dependent PCNA NES.
Dikra Bouayad; Magali Pederzoli-Ribeil; Julie Mocek; Céline Candalh; Jean-Benoît Arlet; Olivier Hermine; Nathalie Reuter; Noélie Davezac; Véronique Witko-Sarsat
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-30
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-10-01     Completed Date:  2012-12-14     Revised Date:  2013-10-10    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  33812-25     Citation Subset:  IM    
INSERM U1016, 75014 Paris, France.
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MeSH Terms
Active Transport, Cell Nucleus
Blotting, Western
Cell Differentiation
Cell Nucleus / metabolism*
Cells, Cultured
Cytoplasm / metabolism*
Fatty Acids, Unsaturated / chemistry
Granulocytes / cytology
HL-60 Cells
HeLa Cells
Karyopherins / metabolism*
Models, Molecular
Neutropenia / metabolism
Neutrophils / cytology*
Proliferating Cell Nuclear Antigen / chemistry*
Receptors, Cytoplasmic and Nuclear / metabolism*
Reg. No./Substance:
0/Fatty Acids, Unsaturated; 0/Karyopherins; 0/Proliferating Cell Nuclear Antigen; 0/Receptors, Cytoplasmic and Nuclear; 0/exportin 1 protein; 87081-35-4/leptomycin B

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