Challenges and Insights in Regulation of p53 and NF‐kappaB Transcription Factors: Making the Case for Cancer Prevention from the Environmental‐Physiological Paradigm

Abstract

The American Cancer Society currently reports that 42% of cancer cases are caused by avoidable risk factors, such as tobacco smoking, low fiber diets and HPV, while the remaining 58% of cases have been correlated with chronic exposure to known and unknown environmental carcinogens and endogenous inflammatory reactive oxygen species. Given the high correlation of acquired mutations in the TP53 (tumor suppression) gene in various stages of cancer progression and the associated misregulation of NF-kappaB (innate immunity and inflammation), there have been numerous efforts to deduce the mechanism of transcriptional regulation of the two families that are also associated with cell cycle regulation, cell proliferation, apoptosis, metabolism, embryonic development and somatic cell differentiation. However, there is no definitive model of p53 or NF-kappaB regulation in the nucleus that can explain how the numerous genes involved in complex cell processes are activated/repressed. The main challenges stem from the sheer structural complexity of each family member, having multiple isoforms, splice variants and post-translational modifications that subsequently interact with different epigenetic and genetic cofactors. We have reported the first crystallographic and biochemical evidence showing the structure-function relationships of key DNA-binding features and regulatory domains in p73 and RelA that play a role in gene activation and repression via DNA response element (RE) sequence recognition. While initial studies show p53 and NF-kappaB family members binding to regulatory regions for hundreds of different genes at canonical DNA RE sequences, there may be a permissive modality in sequence recognition implying the larger importance of epigenetic regulation in tumor suppression or epigenetic mis-regulation in oncogenesis. As transcription is largely regulated in response to environmental stimuli via signaling cascades, the same endogenous factors involved in regulating inflammation, wound healing and cell differentiation, e.g. gut-derived serotonin, may be key to counteracting exogenous factors in cancer onset and progression. Support or Funding Information Molecular Biophysics Training Grant, NIH Grant T32 GM008326; Ruth L. Kirschstein National Research Service Award #T32 CA009523; Diffraction data were collected at BL7-1 of the Stanford/Stanford Synchrotron Radiation Lightsource supported by the Department of Energy and National Institutes of Health [P41RR001209] Comparison of the DNA-binding residues of five structures of the p73 DBD in complex with DNA consensus sequences associated with cell-cycle arrest or apoptosis. Abdul S. Ethayathulla et al. J. Biol. Chem. 2013;288:4744–4754 DNA-binding constants of the p73 S139F DBD mutant and the ΔNp73δ isoform for GGGCA and GAACA sequences associated with cellcycle arrest and apoptosis response elements, respectively. Ciribilli et al. Nucleic Acids Res. 2013 Oct; 41(18): 8637–8653. [Figure and data generated by HT Nguyen and A Ramos] Two RelA homodimers bind tandem κB sites of E-selectin promoter asymmetrically. Maria Carmen Mulero et al. J. Biol. Chem. 2017;292:18821–18830 [Apo] activation domain of RelA inhibits DNA binding. Maria Carmen Mulero et al. J. Biol. Chem. 2017;292:18821–18830 Tandem κB sites act synergistically to activate transcription by RelA. Maria Carmen Mulero et al. J. Biol. Chem. 2017;292:18821–18830 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.