Browsing by Author "Hill, Alexander William"

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    Probing the activity of the inhibitor of growth 1a (ING1a) gene promoter under conditions of cellular stress
    (2024-04-30) Hill, Alexander William; Riabowol, Karl; Billon, Pierre; Williams, Gareth; Shutt, Timothy
    The INhibitor of Growth (ING) family of proteins was initially characterized in 1996 when subtractive hybridization studies revealed a novel type II tumor suppressor, which the authors called ING1. Since then, additional members of the family have been discovered and characterized as important epigenetic regulators, influencing various cellular processes such as stemness, growth, and development. Previous studies have demonstrated that one of the main isoforms of ING1, named ING1a, shows increased expression in senescent cells, with overexpression of the protein resulting in the premature senescence of young fibroblasts. Classically, senescence is a phenotype that occurs as a result of telomere attrition, causing a DNA damage response that ultimately puts the cell in growth arrest. More recent work has shown that the application of various cellular stressors can induce senescence in cells which have otherwise not reached their replicative lifespan, termed stress-induced premature senescence (SIPS). Currently, the relationship between ING1a and cellular stress is incompletely understood, especially at the level of transcriptional control. In the current work, analysis of predicted transcription factors was performed for the ING1a promoter in addition to other stress and senescence-related promoters, demonstrating great overlap between ING1a and senescence marker p16. qPCR analysis of predicted factors showed decreased expression of FOXD1, FOXL1, and MAZ in senescent fibroblasts. ChIP-qPCR against MAZ was performed, validating the transcription factor prediction and showing that MAZ binds to the ING1a promoter. Comparison between promoter-driven constructs and the endogenous promoters revealed that there is likely considerable epigenetic regulation controlling the expression of ING1a, though transcriptional elements sensitive to oxidative stress are likely present.