(1) https://www.ncbi.nlm.nih.gov/pubmed/24631834
Semin Cancer Biol. 2014 Aug;27:52-61. doi: 10.1016/j.semcancer.2014.03.002. Epub 2014 Mar 12.
Atomic basis of CRM1-cargo recognition, release and inhibition.
CRM1 or XPO1 is the major nuclear export receptor in the cell,
which controls the nuclear-cytoplasmic localization of many proteins
and RNAs. CRM1 is also a promising cancer drug target as the transport
receptor is overexpressed in many cancers where some of its cargos are
misregulated and mislocalized to the cytoplasm. Atomic level
understanding of CRM1 function has greatly facilitated recent drug
discovery and development of CRM1 inhibitors to target a variety of
malignancies. Numerous atomic resolution CRM1 structures are now
available, explaining how the exporter recognizes nuclear export signals
in its cargos, how RanGTP and cargo bind with positive cooperativity,
how RanBP1 causes release of export cargos in the cytoplasm and how
diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds
block nuclear export. This review summarizes structure-function studies
that explain CRM1-cargo recognition, release and inhibition.DOI:10.1016/j.semcancer.2014.03.002
(3)
PLoS One. 2011;6(5):e19436. doi: 10.1371/journal.pone.0019436. Epub 2011 May 27.
SARS-CoV 9b protein diffuses into nucleus, undergoes active Crm1 mediated nucleocytoplasmic export and triggers apoptosis when retained in the nucleus.
Sharma K1, Åkerström S, Sharma AK, Chow VT, Teow S, Abrenica B, Booth SA, Booth TF, Mirazimi A, Lal SK.
9b is an accessory protein of the SARS-CoV. It is a small protein of 98 amino acids and its structure has been solved recently. 9b
is known to localize in the extra-nuclear region and has been
postulated to possess a nuclear export signal (NES), however the role of
NES in 9b functioning is not well understood.
In this report, we demonstrate that 9b in the absence of any nuclear localization signal (NLS) enters the nucleus by passive transport. Using various cell cycle inhibitors, we have shown that the nuclear entry of 9b is independent of the cell cycle. Further, we found that 9b interacts with the cellular protein Crm1 and gets exported out of the nucleus using an active NES. We have also revealed that this NES activity influences the half-life of 9b and affects host cell death. We found that an export signal deficient SARS-CoV 9b protein induces apoptosis in transiently transfected cells and showed elevated caspase-3 activity.
In this report, we demonstrate that 9b in the absence of any nuclear localization signal (NLS) enters the nucleus by passive transport. Using various cell cycle inhibitors, we have shown that the nuclear entry of 9b is independent of the cell cycle. Further, we found that 9b interacts with the cellular protein Crm1 and gets exported out of the nucleus using an active NES. We have also revealed that this NES activity influences the half-life of 9b and affects host cell death. We found that an export signal deficient SARS-CoV 9b protein induces apoptosis in transiently transfected cells and showed elevated caspase-3 activity.
Here, we showed that nuclear shuttling of 9b and its interaction with Crm1 are essential for the proper degradation of 9b and blocking the nuclear export of this protein induces apoptosis. This phenomenon may be critical in providing a novel role to the 9b accessory protein of SARS-CoV.
- PMID:
- 21637748
- PMCID:
- PMC3103500
- DOI:
- 10.1371/journal.pone.0019436
- [Indexed for MEDLINE]
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