Leptomycin B Inhibition of Signal-Mediated Nuclear Export by Direct Binding to CRM1

Kudo, Norio; Wolff, Barbara; Sekimoto, Takeyuki; Schreiner, Erwin; Yoneda, Yoshihiro; Yanagida, Mitsuhiro; Horinouchi, Sueharu; Yoshida, Minoru

doi:10.1006/excr.1998.4136

Cited by 771 publications

(654 citation statements)

References 34 publications

Supporting

Mentioning

623

Contrasting

Unclassified

Order By: Relevance

“…In earlier cell culture studies, it was reported that nuclear export of Top IIa is mediated by CRM1, a mechanism, which could be blocked by the CRM1 inhibitor lepotomycin B (LMB). [33][34][35] Our data reveal an in vivo implication of nuclear export mechanisms in Top IIa cytoplasmic localization.…”

Section: Discussionmentioning

confidence: 64%

Topoisomerase IIα mRNA and protein expression in ovarian carcinoma: correlation with clinicopathological factors and prognosis

et al. 2009

View full text Add to dashboard Cite

Topoisomerase IIa (Top IIa) is a nuclear enzyme that plays a central role in DNA metabolism, and is a molecular target for a variety of chemotherapeutic agents. Top IIa has recently gained attention as a biomarker for therapy response and patient survival. In this study, we attempted to assess the feasibility of measuring Top IIa gene expression in RNA, isolated from archival formalin-fixed paraffin-embedded tissue specimens, which are used routinely in pathology laboratories. We have employed a new technique on the basis of magnetic particles' separation and purification of nucleic acids, and evaluated both protein and mRNA expressions from the same routinely processed tissue blocks. We investigated the expression of Top IIa mRNA and protein by real-time reverse transcription polymerase chain reaction and immunohistochemistry, in a cohort of 133 primary ovarian carcinomas, and evaluated the association between Top IIa expression and clincopathological variables as well as patient outcome. Elevated Top IIa mRNA expression was observed in high-grade tumors (P ¼ 0.003) and advanced stage disease (P ¼ 0.011). In univariate Kaplan-Meier analysis, patients with higher expression of Top IIa nuclear protein had a significantly decreased overall survival (P ¼ 0.045). Interestingly, we detected cytoplasmic protein expression of Top IIa in a subset of samples. Cytoplasmic expression of Top IIa was associated with the expression of chromosomal region maintenance/exportin 1 (CRM1)-a nuclear export protein (P ¼ 0.008). Our study suggests that Top IIa overexpression is involved in the progression of ovarian cancer in a subset of the patients. Our results encourage the further evaluation of the prognostic and predictive values of Top IIa expression in ovarian carcinoma, which might help to assess the patients' risk profile, and the planning of an individualized therapy.

show abstract

Section: Discussionmentioning

confidence: 64%

Topoisomerase IIα mRNA and protein expression in ovarian carcinoma: correlation with clinicopathological factors and prognosis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…After exit from the nucleus, the hydrolysis of RanGTP to RanGDP by RanGTPase causes the dissociation of CRM1-cargo complex and thereby releases the cargo into the cytoplasm. This export cycle can be inhibited by the small molecule leptomycin B (LMB) which alkylates Cys529 of CRM1 and blocks its function (Kudo et al, 1999;Kudo et al, 1998).…”

Section: V456 Role Of the Nucleus In The Degradation Of Nes-flucdmentioning

confidence: 99%

Firefly luciferase mutants as sensors of proteome stress

et al. 2011

View full text Add to dashboard Cite

“…Leptomycin B has recently been described as a natural product which binds speci®cally to Crm-1 and inhibits the nuclear export of a wide variety of proteins (Nishi et al, 1994;Fornerod et al, 1997;Kudo et al, 1998), including wild type p53 (Freedman and Levine, 1998;Lain et al, 1999;Stommel et al, 1999). Because inhibition of an acidic protease led to nuclear accumulation of BRCA1, we reasoned that, if BRCA1 degradation required transport to the cytoplasm, leptomycin B might cause nuclear accumulation of BRCA1 in the absence of protease inhibition.…”

Section: Brca1 Protein Accumulated After Alln Has An Increased Half-lifementioning

confidence: 99%

Regulation of BRCA1 by protein degradation

et al. 1999

View full text Add to dashboard Cite

BRCA1, a tumor suppressor protein implicated in hereditary forms of breast and ovarian cancer, is transcriptionally regulated in a proliferation-dependent manner. In this study, we demonstrate a substantial role for proteolysis in regulating the BRCA1 steady-state protein level in several cell lines. N-acetyl-leu-leunorleucinal (ALLN), an inhibitor of the proteasome, calpain, and cathepsins, caused BRCA1 protein to accumulate in the nucleus of several human breast, prostate, and melanoma cell lines which express low or undetectable basal levels of BRCA1 protein, but not in cells with high basal expression of BRCA1. Protease inhibition did not increase BRCA1 synthesis, nor change its mRNA level, but it dramatically prolonged the protein's half-life. In contrast to ALLN, lactacystin and PS341, two speci®c proteasome inhibitors, as well as calpastatin peptide and PD150606, two selective calpain inhibitors, had no e ect on BRCA1 stability, whereas ALLM, an e ective calpain and cathepsin inhibitor but weak proteasome inhibitor, did stimulate accumulation of BRCA1. Moreover, three inhibitors of acidic cysteine proteases, chloroquine, ammonium chloride and ba®lo-mycin, were as e ective as ALLN. These results demonstrate that degradation by a cathepsin-like protease in ®ne balance with BRCA1 transcription is responsible for maintaining the low steady-state level of BRCA1 protein seen in many cancer cells.

show abstract

Leptomycin B Inhibition of Signal-Mediated Nuclear Export by Direct Binding to CRM1

Cited by 771 publications

References 34 publications

Topoisomerase IIα mRNA and protein expression in ovarian carcinoma: correlation with clinicopathological factors and prognosis

Topoisomerase IIα mRNA and protein expression in ovarian carcinoma: correlation with clinicopathological factors and prognosis

Firefly luciferase mutants as sensors of proteome stress

Regulation of BRCA1 by protein degradation

Contact Info

Product

Resources

About