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Distinct p53 isoforms code for opposing transcriptional outcomes.

ABSTRACT: p53 genes are conserved transcriptional activators that respond to stress. These proteins can also downregulate genes, but the mechanisms are not understood and are generally assumed to be indirect. Here, we investigate synthetic and native cis-regulatory elements in Drosophila to examine opposing features of p53-mediated transcriptional control in vivo. We show that transcriptional repression by p53 operates continuously through canonical DNA binding sites that confer p53-dependent transactivation at earlier developmental stages. p53 transrepression is correlated with local H3K9me3 chromatin marks and occurs without the need for stress or Chk2. In sufficiency tests, two p53 isoforms qualify as transrepressors and a third qualifies as a transcriptional activator. Targeted isoform-specific knockouts dissociate these opposing transcriptional activities, highlighting features that are dispensable for transactivation but critical for repression and for proper germ cell formation. Together, these results demonstrate that certain p53 isoforms function as constitutive tissue-specific repressors, raising important implications for tumor suppression by the human counterpart.

SUBMITTER: Wylie A

PROVIDER: S-EPMC9378576 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Distinct p53 isoforms code for opposing transcriptional outcomes.

Wylie Annika A Jones Amanda E AE Das Simanti S Lu Wan-Jin WJ Abrams John M JM

Developmental cell 20220711 15

p53 genes are conserved transcriptional activators that respond to stress. These proteins can also downregulate genes, but the mechanisms are not understood and are generally assumed to be indirect. Here, we investigate synthetic and native cis-regulatory elements in Drosophila to examine opposing features of p53-mediated transcriptional control in vivo. We show that transcriptional repression by p53 operates continuously through canonical DNA binding sites that confer p53-dependent transactivat ...[more]

PMID: 35820415

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Project description:The TP53 gene encodes p53, a transcription factor involved in tumor suppression. However, TP53 also encodes other protein isoforms, some of which can disrupt the tumor suppressor functions of p53 even in the absence of TP53 mutations. In particular, elevated levels of the Δ133TP53 mRNA are detected in many cancer types and can be associated with poorer disease-free survival. We investigated the mechanisms of action of the two proteins translated from the Δ133TP53 mRNA: the Δ133p53α and Δ160p53α isoforms, both of which retain the oligomerization domain of p53. We discovered that the Δ133p53α and Δ160p53α isoforms adopt an altered conformation compared to full-length p53, exposing the PAb240 epitope (RHSVVV), which is inaccessible to the PAb240 antibody in the functional conformation of p53 (reactive to PAb1620). The Δ133p53α and/or Δ160p53α isoforms form hetero-oligomers with p53, regulating the stability, the conformation and the transcriptional activity of the p53 hetero-oligomers. Under basal conditions, Δ133p53α and Δ160p53α, in complex with p53, prevent proteasome-dependent degradation leading to the accumulation of PAb240 reactive Δ133p53α/Δ160p53α/p53 hetero-oligomers without increasing p53 transcriptional activity. Conversely, depletion of endogenous Δ133p53α isoforms in human fibroblasts is sufficient to restore p53 transcriptional activity, towards p53-target genes involved in cell cycle arrest. In the DNA damage response (DDR), PAb240 reactive Δ133p53α/Δ160p53α/p53 hetero-oligomers are highly phosphorylated at Ser15 compared to PAb1620-reactive p53 complexes devoid of Δ133p53α and Δ160p53α. This suggests that PAb240-reactive p53 hetero-oligomers integrate DNA damage signals. Δ133p53α accumulation is a late event in the DDR that depends on p53, but not on its transcriptional activation. The formation of Δ133p53α and p53 complexes increases at later DDR stages. We propose that Δ133p53α isoforms regulate p53 conformation as part of the normal p53 biology, modulating p53 activity and thereby adapting the cellular response to the cell signals.

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Distinct p53 isoforms code for opposing transcriptional outcomes.

Publications

Distinct p53 isoforms code for opposing transcriptional outcomes.

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