Document Detail


Mechanisms regulating the secretion of the promalignancy chemokine CCL5 by breast tumor cells: CCL5's 40s loop and intracellular glycosaminoglycans.
MedLine Citation:
PMID:  22355269     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The chemokine CCL5 (RANTES) plays active promalignancy roles in breast malignancy. The secretion of CCL5 by breast tumor cells is an important step in its tumor-promoting activities; therefore, inhibition of CCL5 secretion may have antitumorigenic effects. We demonstrate that, in breast tumor cells, CCL5 secretion necessitated the trafficking of CCL5-containing vesicles on microtubules from the endoplasmic reticulum (ER) to the post-Golgi stage, and CCL5 release was regulated by the rigidity of the actin cytoskeleton. Focusing on the 40s loop of CCL5, we found that the (43)TRKN(46) sequence of CCL5 was indispensable for its inclusion in motile vesicles, and for its secretion. The TRKN-mutated chemokine reached the Golgi, but trafficked along the ER-to-post-Golgi route differently than the wild-type (WT) chemokine. Based on the studies showing that the 40s loop of CCL5 mediates its binding to glycosaminoglycans (GAG), we analyzed the roles of GAG in regulating CCL5 secretion. TRKN-mutated CCL5 had lower propensity for colocalization with GAG in the Golgi compared to the WT chemokine. Secretion of WT CCL5 was significantly reduced in CHO mutant cells deficient in GAG synthesis, and the WT chemokine acquired an ER-like distribution in these cells, similar to that of TRKN-mutated CCL5 in GAG-expressing cells. The release of WT CCL5 was also reduced after inhibition of GAG presence/synthesis by intracellular expression of heparanase, inhibition of GAG sulfation, and sulfate deprivation. The need for a (43)TRKN(46) motif and for a GAG-mediated process in CCL5 secretion may enable the future design of modalities that prevent CCL5 release by breast tumor cells.
Authors:
Gali Soria; Yaeli Lebel-Haziv; Marcelo Ehrlich; Tsipi Meshel; Adva Suez; Edward Avezov; Perri Rozenberg; Adit Ben-Baruch
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  14     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-02-22     Completed Date:  2012-06-12     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  1-19     Citation Subset:  IM    
Affiliation:
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Motifs / physiology
Amino Acid Sequence
Animals
Blotting, Western
Breast Neoplasms / metabolism*,  secretion
CHO Cells
Cell Line, Tumor
Chemokine CCL5 / chemistry*,  secretion*
Cricetinae
Cricetulus
Enzyme-Linked Immunosorbent Assay
Female
Flow Cytometry
Glycosaminoglycans / chemistry,  metabolism*
Humans
Intracellular Space / metabolism
Microscopy, Confocal
Molecular Sequence Data
Protein Structure, Tertiary
Protein Transport / physiology
Chemical
Reg. No./Substance:
0/CCL5 protein, human; 0/Chemokine CCL5; 0/Glycosaminoglycans
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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