Abstract
Gain‐of‐function (GOF) mutants of p53 upregulate genes implicated in cell proliferation and oncogenesis. Here, we report that GOF p53 induces tumorigenicity through simultaneous activation of key oncogenic pathways including those controlling putative tumor‐initiating cell functions. We determined that in cells expressing p53‐R273H, GOF p53 simultaneously upregulates genes from multiple signaling pathways by recognizing promoters containing distinct transcription factor (TF) binding sites. Our analytical data support a model in which GOF p53 complexes with two TFs on the promoter—a mediator protein, Med17, and a histone acetyl transferase, activating histone acetylation—and enhances gene expression to signal cell proliferation and oncogenesis. Thus, therapeutic inhibition of one GOF p53‐induced pathway would be insufficient to prevent tumor growth as the oncoprotein activates a multitude of parallel pathways. This discovery suggests enormous selection advantage for cancer cells with GOF p53 to induce oncogenic growth, highlighting the problems of cancer therapy.
Highlights
P53 mutation is very common in human lung cancer: 33% in non-small-cell lung cancer to 70% in small-cell lung cancer (Greenblatt et al, 1994)
We show that specific transcription factors (TFs) are involved in mediating GOF p53 binding and transactivation of specific promoters
chromatin immunoprecipitation (ChIP) and RNA-seq reveal sets of genes that are upregulated by p53-R273H and whose regulatory sequences interact with mutant p53 in H1299 cells
Summary
P53 mutation is very common in human lung cancer: 33% in non-small-cell lung cancer to 70% in small-cell lung cancer (Greenblatt et al, 1994). Mutant p53 gain-of-function activity activities are at least partially conducted through the transactivation property of GOF p53 mutants (FreedPastor and Prives, 2012; Muller and Vousden, 2013, 2014; Oren and Rotter, 2010). With the use of chromatin immunoprecipitation (ChIP), we and others have identified a number of promoters where GOF p53 interacts (Vaughan et al, 2012c, 2016); ChIP-seq analysis was performed defining genes that are targets of GOF p53 that might explain different GOF activities of mutant p53 (Do et al, 2012; Stambolsky et al, 2010; Vaughan et al, 2014). We suggest a model to explain GOF p53-mediated gene induction and demonstrate that on the regulatory sequences of the gene that it activates, GOF p53 complexes with two TFs, a member of the mediator complex Med, and a histone acetyl transferase activating histone acetylation fostering expression of oncogenic target genes
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