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  CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis

Connor, M. K., Kotchetkov, R., Cariou, S., Resch, A., Lupetti, R., Beniston, R. G., et al. (2003). CRM1/Ran-mediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. Molecular Biology of the Cell, 14(1), 201-213.

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Genre: Journal Article
Alternative Title : Mol. Biol. Cell

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 Creators:
Connor, M. K., Author
Kotchetkov, R., Author
Cariou, S., Author
Resch, A., Author
Lupetti, R.1, Author           
Beniston, R. G., Author
Melchior, F.2, Author           
Hengst, L.2, Author           
Slingerland, J. M., Author
Affiliations:
1External Organizations, ou_persistent22              
2Former Research Groups, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565145              

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 Abstract: We show that p27 localization is cell cycle regulated and we suggest that active CRM1/RanGTP-mediated nuclear export of p27 may be linked to cytoplasmic p27 proteolysis in early G1. p27 is nuclear in GO and early G1 and appears transiently in the cytoplasm at the G1/S transition. Association of p27 with the exportin CRM1 was minimal in GO and increased markedly during G1-to-S phase progression. Proteasome inhibition in mid-G1 did not impair nuclear import of p27, but led to accumulation of p27 in the cytoplasm, suggesting that export precedes degradation for at least part of the cellular p27 pool. p27- CRM1 binding and nuclear export were inhibited by S10A mutation but not by T187A mutation. A putative nuclear export sequence in p27 is identified whose mutation reduced p27-CRM1 interaction, nuclear export, and p27 degradation. Leptomycin B (LMB) did not inhibit p27-CRM1 binding, nor did it prevent p27 export in vitro or in heterokaryon assays. Prebinding of CRM1 to the HIV-1 Rev nuclear export sequence did not inhibit p27- CRM1 interaction, suggesting that p27 binds CRM1 at a non-LMB- sensitive motif. LMB increased total cellular p27 and may do so indirectly, through effects on other p27 regulatory proteins. These data suggest a model in which p27 undergoes active, CRM1- dependent nuclear export and cytoplasmic degradation in early G1. This would permit the incremental activation of cyclin E- Cdk2 leading to cyclin E-Cdk2-mediated T187 phosphorylation and p27 proteolysis in late G1 and S phase.

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Language(s): eng - English
 Dates: 2003-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 41453
ISI: 000180497300017
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Title: Molecular Biology of the Cell
  Alternative Title : Mol. Biol. Cell
Source Genre: Journal
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Pages: - Volume / Issue: 14 (1) Sequence Number: - Start / End Page: 201 - 213 Identifier: ISSN: 1059-1524