Δ133p53 and Δ160p53 isoforms of the tumor suppressor protein p53 exert dominant-negative effect primarily by co-aggregation

p53 is a tumor suppressor protein with multiple isoforms that have shared or specific functions. However, two of its isoforms, Δ133p53 and Δ160p53, with large N-terminal deletions, can aggressively cause cancer. These isoforms exert a dominant negative effect on full-length p53 (FLp53), although the precise molecular mechanisms are unknown. Here, we investigated the mechanisms of action of Δ133p53 and Δ160p53 isoforms using chromatin immunoprecipitation, luciferase expression, subcellular fractionation, and immunofluorescence assays. Our study elucidates that these DNA-binding deficient p53 isoforms form hetero-tetrameric complexes with FLp53 and disrupt FLp53's DNA binding and transcriptional activities when present in a higher proportion than FLp53 in the tetramer. However, these structurally unstable isoforms promote vigorous protein aggregation involving FLp53, disrupting its structure and sequestering it in the cytoplasmic and nuclear aggregates, thereby limiting its availability to function as a transcription activator protein. Thus, co-aggregation of Δ133p53 and Δ160p53 with FLp53, rather than hetero-tetramerization, is the primary factor contributing to their dominant-negative effect. Modulating the stability and aggregation of p53 isoforms could be a novel strategy for cancer therapy.