Tumor suppressor p53 integrates host defense and cell fate during bacterial pneumonia
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE38420 | GEO | 2013/04/19
SECONDARY ACCESSION(S): PRJNA167822
REPOSITORIES: GEO
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Project description:FOXQ1 transcription factors is highly induced in several types of carcinomas where it promotes tumour growth and metastasis, however, the molecular mechanisms leading to FOXQ1 deregulation in cancer are incompletely understood. Here, we used a CRISPR/Cas9-based genomic locus proteomics (GLoPro) to discover transcriptional regulators of FOXQ1 and identified the tumour suppressor p53 as a transcriptional repressor of FOXQ1 expression. ChIP-qPCR as well as complementary gain and loss-of-function assays in model cell lines indicated that p53 has multiple binding sites close to the transcription start site of the FOXQ1 promoter, and that it suppresses FOXQ1 expression in various cell types. Consistently, pharmacological activation of p53 using nutlin-3 or doxorubicin reduced FOXQ1 mRNA and protein levels in colorectal cancer cell lines harboring wild type p53. In conclusion, these results suggest that mutational loss-of-function of p53, a hallmark feature of many types of cancer, de-represses FOXQ1, which accelerates tumour progression.
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Project description:p53 mutations are believed to correlate with poor patient survival, as mutations abolish the transcriptional function of wild-type p53 in the DNA damage response and mutant p53 gain-of-function activities enhance drug resistance. Moreover, p53 also exhibits non-transcriptional apoptotic activity with yet unclear in vivo relevance for tumor suppression and cancer therapy. We have generated mice expressing a unique p53 mutant (R178E, human R181E) that is DNA binding deficient without alterations in the global structure or DNA binding surface. The aim of this study is to use this new mouse model to demonstrate that a DNA binding-deficient p53 mutant can drive tumor development while retaining non-transcriptional apoptotic activities.
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Project description:The tumor suppressor protein p53 is a transcription factor that is referred to as the “guardian of the genome” and plays an important role in cancer development. P53 is active as a tetramer; the S100β homodimer binds to the intrinsically disordered C-terminus of p53, affecting its transcriptional activity. The p53/S100β complex is regarded as highly promising therapeutic target in cancer. It has been suggested that S100β exerts its oncogenic effects by altering the p53 oligomeric state. Our aim was to study the structures and oligomerization behavior of different p53/S100β complexes by electrospray ionization mass spectrometry (ESI-MS), cross-linking mass spectrometry (XL-MS), and surface plasmon resonance (SPR). For this, wild-type p53 and single amino acid variants, representing different oligomeric states of p53 (tetrameric wild-type, dimeric L344A variant, and monomeric L344P variant) were individually investigated regarding their binding behavior towards S100β. The stoichiometry of the different p53/S100β complexes were determined by ESI-MS showing that tetrameric, dimeric, and monomeric p53 variants all bind to an S100β dimer. In addition, XL-MS revealed the topologies of the p53/S100β complexes to be independent of p53’s oligomeric state. With SPR, the thermodynamic parameters were determined for S100β binding to tetrameric, dimeric or monomeric p53 variants. Our data prove that the S100β homodimer binds to different oligomeric states of p53 with identical stoichiometries and similar binding affinities. This emphasizes the need for alternative explanations to describe the molecular mechanisms underlying p53/S100β interaction.
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