The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop.
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.
Mesh Terms:
Apoptosis, Cell Aging, Cell Line, Tumor, Cycloheximide, Cytokines, DNA Primers, Feedback, Physiological, Flow Cytometry, Fluorescent Antibody Technique, Indirect, HEK293 Cells, Humans, Immunoblotting, Immunohistochemistry, Immunoprecipitation, NAD, Nicotinamide Phosphoribosyltransferase, Polymerase Chain Reaction, Proto-Oncogene Proteins c-myc, RNA Interference, Sirtuin 1, Tumor Suppressor Proteins, Ubiquitination
Apoptosis, Cell Aging, Cell Line, Tumor, Cycloheximide, Cytokines, DNA Primers, Feedback, Physiological, Flow Cytometry, Fluorescent Antibody Technique, Indirect, HEK293 Cells, Humans, Immunoblotting, Immunohistochemistry, Immunoprecipitation, NAD, Nicotinamide Phosphoribosyltransferase, Polymerase Chain Reaction, Proto-Oncogene Proteins c-myc, RNA Interference, Sirtuin 1, Tumor Suppressor Proteins, Ubiquitination
Proc. Natl. Acad. Sci. U.S.A.
Date: Jan. 24, 2012
PubMed ID: 22190494
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