Profiling of novel p53-inducing compounds
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE12666 | GEO | 2010/10/01
SECONDARY ACCESSION(S): PRJNA112735
REPOSITORIES: GEO
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Project description:Ceramides are important participants of signal transduction, regulating fundamental cellular processes. Here we report the mechanism for activation of p53 tumor suppressor by C16-ceramide. C16-ceramide tightly binds within the p53 DNA binding domain (Kd ~ 60 nM), in close vicinity to the Box V motif. This interaction is highly selective towards the ceramide acyl chain length with its C10 atom being proximal to Ser240 and Ser241. Ceramide binding stabilizes p53 and disrupts its complex with E3 ligase MDM2 leading to the p53 accumulation, nuclear translocation and activation of the downstream targets. This is a novel physiological mechanism of p53 activation, which is fundamentally different from the canonical p53 regulation through protein-protein interactions or post-translational modifications. The discovered mechanism is triggered by serum or folate deprivation implicating it in the cellular response to nutrient/metabolic stress. Our study establishes C16-ceramide as the first natural small molecule activating p53 through the direct binding.
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Project description:A better understanding of how p53 differentially activates cell cycle arrest or cell death is important to maximize benefits of therapeutic strategies dependant by wild-type p53. Here, we report that activation of pro-apoptotic p53 transcriptional targets in colorectal cancer cells imposes a critical, targetable dependence on the long splice form of the caspase-8 regulator FLIP (FLIPL) for survival. Upon Nutlin-3A induced stabilisation p53 directly upregulates FLIPL expression in a manner dependent on Class-I HDAC activity. Preventing FLIPL upregulation with the clinically relevant Class-I selective inhibitor Entinostat promotes apoptosis in response to Nutlin-3A , which predominantly induces growth arrest despite upregulating a range of pro-apoptotic target genes. Cell death in response to Nutlin-3A in FLIPL-depleted cells is mediated through two of p53's canonical transcriptional targets TRAIL-R2 and BAX and is caspase-8-dependent. This work uncovers novel, clinically relevant biology that identifies FLIPL as a key target for overcoming resistance to p53-activating agents.
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Project description:Primary objectives: The primary objective of the study is to assess whether the administration of p53-SLP together with the local application of imiquimod or the injection of interferon-alfa is safe and able to induce an immune response specific to p53.
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