Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Residual tumor suppressor activities of tumorigenic p53 mutants enhance survival under chemotherapy

ABSTRACT: 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.

INSTRUMENT(S): Illumina HiSeq 1500

ORGANISM(S): Mus musculus

SUBMITTER: Oleg Timofeev

PROVIDER: E-MTAB-6774 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Recently, more than a thousand large intergenic non-coding RNAs (lincRNAs) have been reported. These RNAs are evolutionarily conserved in mammalian genomes and thus presumably function in diverse biological processes. Here, we report the identification of lincRNAs that are regulated by p53. One of these lincRNAs (lincRNA-p21) serves as a repressor in p53-dependent transcriptional responses. Inhibition of lincRNA-p21 affects the expression of hundreds of gene targets enriched for genes normally repressed by p53. The observed transcriptional repression by lincRNA-p21 is mediated through the physical association with hnRNP-K. This interaction is required for proper genomic localization of hnRNP-K at repressed genes and regulation of p53 mediated apoptosis. We propose a model whereby transcription factors activate lincRNAs that serve as key repressors by physically associating with repressive complexes and modulating their localization to sets of previously active genes. Gene expression profiles of different p53 inducible mouse embryonic fibroblasts (p53LSL/LSL MEFs) across different time points after DNA damage. A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 transcriptional response. [1] MEF profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration or adenoGFP as control for 24h and treated with 500nM doxorubicin for the indicated times. [2] hnRNPKKD profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration for 24h, transfected with siRNA oligos targeting different transcripts for 24h and then treated with 100nM doxorubicin for 13h. [3] lincP21KD profiling: p53 LSL/LSL MEFs were treated with adenoCRE for p53 restoration for 24h, transfected with siRNA oligos targeting different transcripts for 24h and then treated with 100nM doxorubicin for 13h. [4] RAS profiling: For p53 restoration, cultured tumor cell lines were incubated with 500nM 4-hydroxytamoxifen for the indicated times.

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Residual tumor suppressor activities of tumorigenic p53 mutants enhance survival under chemotherapy

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