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Vol. 14, Issue 1, 201-213, January 2003
and
Molecular and Cell Biology, Sunnybrook & Women's
College Health Science Centre, 2075 Bayview Ave, Toronto, Ontario,
Canada, M4N 3M5; and Max Planck Institute for Biochemistry,
Martinsried, 82152, Germany
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 G0
and early G1 and appears transiently in the cytoplasm at the G1/S
transition. Association of p27 with the exportin CRM1 was minimal in G0
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.
Corresponding authors. E-mail address:
jslingerland{at}med.miami.edu or hengst{at}biochem.mpg.de
§
Present address: University of Miami Sylvester Comprehensive
Cancer Center, Division of Hematology Oncology, Miami Florida, 33133
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