ABSTRACT
Despite the prominent pro-apoptotic role of p53, this protein has also been shown to promote cell survival in response to metabolic stress. However, the specific mechanism by which p53 protects cells from metabolic stress-induced death is unknown. Earlier we reported that carnitine palmitoyltransferase 1C (CPT1C), a brain-specific member of a family of mitochondria-associated enzymes that have a central role in fatty acid metabolism promotes cell survival and tumor growth. Unlike other members of the CPT family, the subcellular localization of CPT1C and its cellular function remains elusive. Here, we report that CPT1C is a novel p53-target gene with a bona fide p53-responsive element within the first intron. CPT1C is upregulated in vitro and in vivo in a p53-dependent manner. Interestingly, expression of CPT1C is induced by metabolic stress factors such as hypoxia and glucose deprivation in a p53 and AMP activated kinase-dependent manner. Furthermore, in a murine tumor model, depletion of Cpt1c leads to delayed tumor development and a striking increase in survival. Taken together, our results indicate that p53 protects cells from metabolic stress via induction of CPT1C and that CPT1C may have a crucial role in carcinogenesis. CPT1C may therefore represent an exciting new therapeutic target for the treatment of hypoxic and otherwise treatment-resistant tumors.
Subject(s)
Carnitine O-Palmitoyltransferase/metabolism , Neurofibromatosis 1/metabolism , Tumor Suppressor Protein p53/metabolism , AMP-Activated Protein Kinases/genetics , AMP-Activated Protein Kinases/metabolism , Animals , Brain/enzymology , Carnitine O-Palmitoyltransferase/genetics , Cell Hypoxia , Cell Line , Cell Proliferation , Disease Models, Animal , Mice , Mice, Inbred C57BL , Mice, Knockout , Mitochondria/metabolism , Neurofibromatosis 1/mortality , Neurofibromatosis 1/pathology , Neurofibromin 1/deficiency , Neurofibromin 1/genetics , Neurofibromin 1/metabolism , Promoter Regions, Genetic , RNA, Messenger/metabolism , Transcription, Genetic , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Protein p53/genetics , Up-RegulationABSTRACT
Regulation of the activator protein-1 (AP-1) complex is very intricate because it involves phosphorylation state, protein-protein, and protein-DNA interactions. In these studies, the regulation of AP-1 activity, with emphasis on c-fos and c-jun regulation, was investigated using cannabinol (CBN) in primary mouse splenocytes in vitro. Cannabinoid compounds exhibit immunosuppressive actions that are putatively mediated through Gi-protein coupled receptors that negatively regulate adenylate cyclase. However, recent studies suggest that cannabinoids modulate other signaling cascades. Indeed, we demonstrate that CBN inhibited binding to AP-1-containing sites from the interleukin-2 promoter. This inhibition of binding was, in part, due to decreased nuclear expression of c-fos and c-jun. We further determined that the effects of CBN were due to posttranslational modifications of these phosphoproteins and showed that CBN inhibited the activation of ERK MAP kinases. Thus, cannabinoid-induced immunosuppression involves disruption of the ERK signaling cascade.
