p53 and aging
The p53 transcription factor is best known as a tumor suppressor but also plays fundamental roles in aging, metabolism, and stem cell biology. A naturally occurring p53 isoform, called Δ40p53 (or ΔNp53), causes accelerated aging in mice when expressed together with WTp53. Importantly, mixed Δ40p53:WTp53 tetramers are essential for the accelerated aging phenotype; Δ40p53 homozygous mice resemble p53-null mice and do not age rapidly (Scrable et al. Genes Dev 2004).
Because p53 functions as a tetramer (i.e. it binds DNA as a tetramer), co-expression of Δ40p53 and WTp53 will form Δ40p53:WTp53 tetramers with mixed stoichiometry. This presents a significant barrier to understanding how Δ40p53 specifically affects cellular function, because co-expression of Δ40p53 and WTp53 will result in tetramer heterogeneity, including formation of WTp53 tetramers. To circumvent this problem, we expressed Δ40p53:WTp53 as a single transcript that ensured a 2:2 stoichiometry (Δ40p53:WTp53) within the tetramer (see Figure). This strategy, which is based off the structure of the native WTp53 tetramer (Orlova et al. EMBO 2006), eliminates confounding issues associated with Δ40p53 and WTp53 co-expression and allows clear delineation of cellular changes triggered by Δ40p53:WTp53 vs. WTp53.
Aging is a complex process that is fundamental to biology. An improved understanding of the molecular mechanisms that contribute to cellular stress responses and homeostasis could ultimately reveal strategies to de-couple aging, and its associated diseases, from chronological time. Among the various models for aging, a common theme includes stochastic and/or heritable epigenetic changes that gradually alter metabolic pathways and global gene expression patterns. Such mechanisms appear to represent a fundamental requirement for aging, as biological effects manifest over time. Based upon our proof-of-concept studies involving comparative gene expression and metabolomics data for Δ40p53:WTp53 vs. WTp53 (Lin et al. Aging Cell 2013), it appears that epigenetic changes might be triggered by Δ40p53:WTp53 expression. Ongoing projects are using “next generation” methods to explore how Δ40p53 alters WTp53 function, and future studies will assess how Δ40p53:WTp53 expression might alter DNA methylation and histone modification patterns, with potential implications for normal, physiological aging.
Lab publications related to ∆40p53 and aging:
Levandowski, CB; Jones, T; Gruca, M; Ramamoorthy, S; Dowell, RD;* Taatjes, DJ.* The naturally occurring ∆40p53 isoform inhibits eRNA transcription and enables context-specific regulation during p53 activation. 2020, Cell Press pre-print server: ssrn.com/abstract=3624472
Lin, SC; Karoly, ED; Taatjes, DJ. The human ∆Np53 isoform triggers metabolic and gene expression changes that activate mTOR and alter mitochondrial function. Aging Cell 2013, 12: 863 – 872.
Lin, SC; Taatjes, DJ. ∆Np53 and aging. Aging (Albany NY) 2013, 5: 717 – 718.