Transcription-dependent and -independent functions of Drosophila p53 isoforms in the induction of apoptosis and senescence-associated tumorigenesis.

Abstract

The tumor suppressor p53 orchestrates critical cellular responses to stress, including cell cycle arrest, DNA repair, senescence, and apoptosis. While extensive research has elucidated many aspects of p53 function, the isoform-specific mechanisms governing cell fate decisions remain incompletely understood. Here, we leverage the simplified p53 gene architecture in Drosophila to systematically dissect the apoptotic and tumorigenic potential of individual p53 isoforms, uncovering fundamental differences in their function. Our findings indicate that whereas p53-A and p53-E pro-apoptotic activity strictly depends on the proliferative state of the cell, the full-length p53-B isoform -structurally analogous to vertebrate p53- induces apoptosis independently of cell cycle status. Furthermore, p53-B triggers apoptosis via transcription-independent mechanisms involving direct activation of the initiator caspase Dronc. We also show that all isoforms promote tumorigenesis by inducing the JNK pathway and the formation of senescent cells through distinct mechanisms in cells that are unable to complete the apoptosis program. Importantly, some of these findings are largely recapitulated by human versions of p53 when ectopically expressed in Drosophila cells. Together our data, reveal that p53 isoforms govern apoptosis and senescence-associated tumorigenesis through distinct molecular mechanisms, providing new insights into the complexity of p53-mediated cell fate determination.