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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Bourguignon, Lilly Y. W. Xia, Weiliang Wong, Gabriel |
| Description | Author Affiliation: Bourguignon LY ( Department of Medicine, Endocrine Unit (111N2), University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, CA 94121, USA. lilly.bourguignon@ucsf.edu) |
| Abstract | In this study we have investigated hyaluronan (HA)-mediated CD44 (an HA receptor) interactions with p300 (a histone acetyltransferase) and SIRT1 (a histone deacetylase) in human breast tumor cells (MCF-7 cells). Specifically, our results indicate that HA binding to CD44 up-regulates p300 expression and its acetyltransferase activity that, in turn, promotes acetylation of beta-catenin and NFkappaB-p65 leading to activation of beta-catenin-associated T-cell factor/lymphocyte enhancer factor transcriptional co-activation and NFkappaB-specific transcriptional up-regulation, respectively. These changes then cause the expression of the MDR1 (P-glycoprotein/P-gp) gene and the anti-apoptotic gene Bcl-x(L) resulting in chemoresistance in MCF-7 cells. Our data also show that down-regulation of p300, beta-catenin, or NFkappaB-p65 in MCF-7 cells (by transfecting cells with p300-, beta-catenin-, or NFkappaB-p65-specific small interfering RNA) inhibits the HA/CD44-mediated beta-catenin/NFkappaB-p65 acetylation and abrogates the aforementioned transcriptional activities. Subsequently, there is a significant decrease in both MDR1 and Bcl-x(L) gene expression and an enhancement in caspase-3 activity and chemosensitivity in the breast tumor cells. Further analyses indicate that activation of SIRT1 (deacetylase) by resveratrol (a natural antioxidant) induces SIRT1-p300 association and acetyltransferase inactivation, leading to deacetylation of HA/CD44-induced beta-catenin and NFkappaB-p65, inhibition of beta-catenin-T-cell factor/lymphocyte enhancer factor and NFkappaB-specific transcriptional activation, and the impairment of MDR1 and Bcl-x(L) gene expression. All these multiple effects lead to an activation of caspase-3 and a reduction of chemoresistance. Together, these findings suggest that the interactions between HA/CD44-stimulated p300 (acetyltransferase) and resveratrol-activated SIRT1 (deacetylase) play pivotal roles in regulating the balance between cell survival versus apoptosis, and multidrug resistance versus sensitivity in breast tumor cells. |
| ISSN | 00219258 |
| e-ISSN | 1083351X |
| Journal | Journal of Biological Chemistry |
| Issue Number | 5 |
| Volume Number | 284 |
| Language | English |
| Publisher | American Society for Biochemistry and Molecular Biology (United States) |
| Publisher Date | 2009-01-30 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antigens, CD44 Metabolism Breast Neoplasms Gene Expression Regulation, Neoplastic Drug Effects Genes, MDR Hyaluronic Acid Pharmacology NF-kappa B Sirtuins Bcl-X Protein Genetics Beta Catenin P300-CBP Transcription Factors Pathology Cell Line, Tumor Drug Resistance, Neoplasm Protein Binding Signal Transduction Sirtuin 1 Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Biochemistry Molecular Biology |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Biochemistry Molecular Biology |
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