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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Diebold, Joachim Menssen, Antje Kapelle, Karsten Lüscher, Bernhard Vervoorts, Jörg Hermeking, Heiko Hydbring, Per Larsson, Lars-gunnar |
| Description | Author Affiliation: Menssen A ( Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, D-80337 Munich, Germany. antje.menssen@med.uni-muenchen.de); |
| Abstract | Silent information regulator 1 (SIRT1) represents an NAD(+)-dependent deacetylase that inhibits proapoptotic factors including p53. Here we determined whether SIRT1 is downstream of the prototypic c-MYC oncogene, which is activated in the majority of tumors. Elevated expression of c-MYC in human colorectal cancer correlated with increased SIRT1 protein levels. Activation of a conditional c-MYC allele induced increased levels of SIRT1 protein, NAD(+), and nicotinamide-phosphoribosyltransferase (NAMPT) mRNA in several cell types. This increase in SIRT1 required the induction of the NAMPT gene by c-MYC. NAMPT is the rate-limiting enzyme of the NAD(+) salvage pathway and enhances SIRT1 activity by increasing the amount of NAD(+). c-MYC also contributed to SIRT1 activation by sequestering the SIRT1 inhibitor deleted in breast cancer 1 (DBC1) from the SIRT1 protein. In primary human fibroblasts previously immortalized by introduction of c-MYC, down-regulation of SIRT1 induced senescence and apoptosis. In various cell lines inactivation of SIRT1 by RNA interference, chemical inhibitors, or ectopic DBC1 enhanced c-MYC-induced apoptosis. Furthermore, SIRT1 directly bound to and deacetylated c-MYC. Enforced SIRT1 expression increased and depletion/inhibition of SIRT1 reduced c-MYC stability. Depletion/inhibition of SIRT1 correlated with reduced lysine 63-linked polyubiquitination of c-Myc, which presumably destabilizes c-MYC by supporting degradative lysine 48-linked polyubiquitination. Moreover, SIRT1 enhanced the transcriptional activity of c-MYC. Taken together, these results show that c-MYC activates SIRT1, which in turn promotes c-MYC function. Furthermore, SIRT1 suppressed cellular senescence in cells with deregulated c-MYC expression and also inhibited c-MYC-induced apoptosis. Constitutive activation of this positive feedback loop may contribute to the development and maintenance of tumors in the context of deregulated c-MYC. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 109 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2012-02-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Apoptosis Physiology Cell Aging Cytokines Metabolism Feedback, Physiological Nicotinamide Phosphoribosyltransferase Proto-Oncogene Proteins C-myc Sirtuin 1 Tumor Suppressor Proteins Cell Line, Tumor Cycloheximide DNA Primers Genetics Flow Cytometry Fluorescent Antibody Technique, Indirect HEK293 Cells Immunoblotting Immunohistochemistry Immunoprecipitation NAD Polymerase Chain Reaction RNA Interference Antagonists & Inhibitors Isolation & Purification Ubiquitination Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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