scholarly journals Engineering chromosome region maintenance 1 fragments that bind to nuclear export signals

2019 ◽  
Vol 29 (6) ◽  
pp. 1366-1372 ◽  
Author(s):  
Yuqin Lei ◽  
Qi An ◽  
Yuqing Zhang ◽  
Ping Luo ◽  
Youfu Luo ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Chromosome Region ◽  
Chromosome Region Maintenance

scholarly journals A Carboxyl Leucine-Rich Region of Parathyroid Hormone-Related Protein Is Critical for Nuclear Export

Endocrinology ◽  
2006 ◽  
Vol 147 (2) ◽  
pp. 990-998 ◽  
Author(s):  
Jared C. Pache ◽  
Douglas W. Burton ◽  
Leonard J. Deftos ◽  
Randolph H. Hastings
Keyword(s):  
Amino Acid ◽  
Nuclear Export ◽  
Chromosome Region ◽  
Nuclear Export Signal ◽  
Wild Type ◽  
Leptomycin B ◽  
Intact Cells ◽  
Parathyroid Hormone Related Protein ◽  
Truncation Mutant ◽  
Chromosome Region Maintenance

PTHrP is an oncofetal protein with distinct proliferative and antiapoptotic roles that are affected by nucleocytoplasmic shuttling. The protein’s nuclear export is sensitive to leptomycin B, consistent with a chromosome region maintenance protein 1-dependent pathway. We determined that the 109–139 region of PTHrP was involved in its nuclear export by demonstrating that a C-terminal truncation mutant, residues 1–108, exports at a reduced rate, compared with the wild-type 139 amino acid isoform. We searched for potential nuclear export sequences within the 109–139 region, which is leucine rich. Comparisons with established nuclear export sequences identified a putative consensus signal at residues 126–136. Deletion of this region resulted in nuclear export characteristics that closely matched those of the C-terminal truncation mutant. Confocal microscopic analyses of transfected 293, COS-1, and HeLa cells showed that steady-state nuclear levels of the truncated and deletion mutants were significantly greater than levels of wild-type PTHrP and were unaffected by leptomycin B, unlike the wild-type protein. In addition, both mutants demonstrated greatly reduced nuclear export with assays using nuclear preparations and intact cells. Based on these results, we conclude that the 126–136 amino acid sequence closely approximates the structure of a chromosome region maintenance protein 1-dependent leucine-rich nuclear export signal and is critical for nuclear export of PTHrP.

Involvement of chromosome region maintenance 1 (CRM1) in the formation and progression of esophageal squamous cell carcinoma

2014 ◽  
Vol 31 (9) ◽  
Author(s):  
Xiaojing Yang ◽  
Lei Cheng ◽  
Li Yao ◽  
Hanru Ren ◽  
Shu Zhang ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Esophageal Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Chromosome Region ◽  
Chromosome Region Maintenance

scholarly journals Structural determinants of nuclear export signal orientation in binding to exportin CRM1

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Ho Yee Joyce Fung ◽  
Szu-Chin Fu ◽  
Chad A Brautigam ◽  
Yuh Min Chook
Keyword(s):  
Crystal Structures ◽  
Nuclear Export ◽  
Chromosome Region ◽  
Nuclear Export Signal ◽  
Opposite Orientation ◽  
Structural Determinants ◽  
Large Expansion ◽  
Export Signal

The Chromosome Region of Maintenance 1 (CRM1) protein mediates nuclear export of hundreds of proteins through recognition of their nuclear export signals (NESs), which are highly variable in sequence and structure. The plasticity of the CRM1-NES interaction is not well understood, as there are many NES sequences that seem incompatible with structures of the NES-bound CRM1 groove. Crystal structures of CRM1 bound to two different NESs with unusual sequences showed the NES peptides binding the CRM1 groove in the opposite orientation (minus) to that of previously studied NESs (plus). Comparison of minus and plus NESs identified structural and sequence determinants for NES orientation. The binding of NESs to CRM1 in both orientations results in a large expansion in NES consensus patterns and therefore a corresponding expansion of potential NESs in the proteome.

scholarly journals Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer

2019 ◽  
Vol 20 (19) ◽  
pp. 4826 ◽  
Author(s):  
Rachel Sexton ◽  
Zaid Mahdi ◽  
Rahman Chaudhury ◽  
Rafic Beydoun ◽  
Amro Aboukameel ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Nuclear Export ◽  
Gastric Cancer Cell ◽  
Clinical Investigation ◽  
Chromosome Region ◽  
Specific Inhibitor ◽  
Anti Tumor Activity

Gastric cancer remains an unmet clinical problem in urgent need of newer and effective treatments. Here we show that the nuclear export protein, Exportin 1 (XPO1, chromosome region maintenance 1 or CRM1), is a promising molecular target in gastric cancer. We demonstrate significant overexpression of XPO1 in a cohort of histologically diverse gastric cancer patients with primary and metastatic disease. XPO1 RNA interference suppressed gastric cancer cell growth. Anti-tumor activity was observed with specific inhibitor of nuclear export (SINE) compounds (selinexor/XPOVIO), second-generation compound KPT-8602/eltanexor, KPT-185 and +ve control Leptomycin B in three distinct gastric cancer cell lines. SINE compounds inhibited gastric cancer cell proliferation, disrupted spheroid formation, induced apoptosis and halted cell cycle progression at the G1/S phase. Anti-tumor activity was concurrent with nuclear retention of tumor suppressor proteins and inhibition of colony formation. In combination studies, SINE compounds enhanced the efficacy of nab-paclitaxel in vitro and in vivo. More significantly, using non-coding RNA sequencing studies, we demonstrate for the first time that SINE compounds can alter the expression of non-coding RNAs (microRNAs and piwiRNAs). SINE treatment caused statistically significant downregulation of oncogenic miR-33b-3p in two distinct cell lines. These studies demonstrate the therapeutic significance of XPO1 in gastric cancer that warrants further clinical investigation.

Preclinical activity of SL-801, a reversible inhibitor of Exportin-1 (XPO1)/Chromosome Region Maintenance-1 (CRM1) in solid and hematologic cancers.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. e13543-e13543
Author(s):  
Janice Chen ◽  
Christopher L. Brooks ◽  
Peter McDonald ◽  
Jonathan D. Schwartz ◽  
Keiichi Sakakibara ◽  
...  
Keyword(s):  
Chromosome Region ◽  
Reversible Inhibitor ◽  
Chromosome Region Maintenance

scholarly journals A Regulated Nucleocytoplasmic Shuttle Contributes to Bright's Function as a Transcriptional Activator of Immunoglobulin Genes

2006 ◽  
Vol 26 (6) ◽  
pp. 2187-2201 ◽  
Author(s):  
Dongkyoon Kim ◽  
Philip W. Tucker
Keyword(s):  
Cell Cycle ◽  
Growth Factor ◽  
Nuclear Matrix ◽  
Nuclear Export ◽  
Cellular Localization ◽  
Cell Cycle Progression ◽  
Chromosome Region ◽  
Nuclear Export Signal ◽  
Variable Region ◽  
Dependent Manner

ABSTRACT Bright/ARID3a has been implicated in mitogen- and growth factor-induced up-regulation of immunoglobulin heavy-chain (IgH) genes and in E2F1-dependent G1/S cell cycle progression. For IgH transactivation, Bright binds to nuclear matrix association regions upstream of certain variable region promoters and flanking the IgH intronic enhancer. While Bright protein was previously shown to reside within the nuclear matrix, we show here that a significant amount of Bright resides in the cytoplasm of normal and transformed B cells. Leptomycin B, chromosome region maintenance 1 (CRM1) overexpression, and heterokaryon experiments indicate that Bright actively shuttles between the nucleus and the cytoplasm in a CRM1-dependent manner. We mapped the functional nuclear localization signal to the N-terminal region of REKLES, a domain conserved within ARID3 paralogues. Residues within the C terminus of REKLES contain its nuclear export signal, whose regulation is primarily responsible for Bright shuttling. Growth factor depletion and cell synchronization experiments indicated that Bright shuttling during S phase of the cell cycle leads to an increase in its nuclear abundance. Finally, we show that shuttle-incompetent Bright point mutants, even if sequestered within the nucleus, are incapable of transactivating an IgH reporter gene. Therefore, regulation of Bright's cellular localization appears to be required for its function.

Sign in / Sign up

Export Citation Format

Share Document