title: The c-MYC oncoprotein, the NAMPT enzyme, the SIRT1-inhibitor DBC1, and the SIRT1 deacetylase form a positive feedback loop.
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.
authors.affiliation: Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University Munich, D-80337 Munich, Germany. antje.menssen@med.uni-muenchen.de
authors.forename: Antje
authors.initials: A
authors.lastname: Menssen
authors.forename: Per
authors.initials: P
authors.lastname: Hydbring
authors.forename: Karsten
authors.initials: K
authors.lastname: Kapelle
authors.forename: Jörg
authors.initials: J
authors.lastname: Vervoorts
authors.forename: Joachim
authors.initials: J
authors.lastname: Diebold
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.forename: Lars-Gunnar
authors.initials: LG
authors.lastname: Larsson
authors.forename: Heiko
authors.initials: H
authors.lastname: Hermeking
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology*; D003513:Cycloheximide; D016207:Cytokines / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D025461:Feedback, Physiological / Q000502:physiology*; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D009243:NAD / Q000378:metabolism; D009419:Nerve Tissue Proteins; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034622:RNA Interference; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C112308:BRINP1 protein, human; D018797:Cell Cycle Proteins; D016207:Cytokines; D017931:DNA Primers; C489427:MYC protein, human; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; D025521:Tumor Suppressor Proteins; D009243:NAD; D003513:Cycloheximide; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1