The Δ133p53 Isoforms, Tuners of the p53 Pathway

Simple Summary TP53, the most frequently mutated gene in human cancers, has a key role in the maintenance of the genetic stability and, thus, in preventing tumor development. The p53-dependent responses were long thought to be solely driven by canonical p53 alpha. However, it is now known that TP53 physiologically expresses at least 12 p53 isoforms including Delta 133p53 alpha, Delta 133p53 beta and Delta 133p53 gamma. The Delta 133p53 isoforms are potent modulators of the p53 pathway that regulate critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. This review aims to summarize the current knowledge on the Delta 133p53 isoforms and how they contribute to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies. The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Delta 133p53 isoforms (Delta 133p53 alpha, Delta 133p53 beta and Delta 133p53 gamma), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Delta 133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Delta 133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.