A novel regulatory circuit between p53 and GFI1 controls induction of apoptosis in T cells

Charles Vadnais,Tarik Möröy,Riyan Chen,Pierre-Jacques Hamard,James J Manfredi,Jennifer Fraszczak

doi:10.1038/s41598-019-41684-2

Abstract

Here we demonstrate a mode of reciprocal regulation between GFI1 and p53 that controls the induction of apoptosis in T cells. We show that GFI1 prevents induction of p53 dependent apoptosis by recruiting LSD1 to p53, which leads to the demethylation of its C-terminal domain. This is accompanied by a decrease of the acetylation of lysine 117 within the core domain of the murine p53 protein, which is required for transcriptional induction of apoptosis. Our results support a model in which the effect of GFI1’s regulation of methylation at the c-terminus of p53 is ultimately mediated through control of acetylation at lysine 117 of p53. We propose that GFI1 acts prior to the occurrence of DNA damage to affect the post-translational modification state and limit the subsequent activation of p53. Once activated, p53 then transcriptionally activates GFI1, presumably in order to re-establish the homeostatic balance of p53 activity. These findings have implications for the activity level of p53 in various disease contexts where levels of GFI1 are either increased or decreased.

Highlights

GFI1 is a protein mainly known as a transcription factor involved in hematopoietic cell differentiation by repressing key target genes in multi-potent precursor cells in order to direct their lineage commitment
Further Co-IP experiments showed that the interaction between the two proteins is unaffected by the presence of benzonase or ethidium bromide (EtBr), indicating that the p53/GFI1 interaction is independent of DNA binding (Fig. 1F,G, Supplementary Fig. 1B)
Our results indicate that a regulatory circuit exists between GFI1 and p53 that controls the induction of apoptosis in T cells

Summary

Introduction

GFI1 is a protein mainly known as a transcription factor involved in hematopoietic cell differentiation by repressing key target genes in multi-potent precursor cells in order to direct their lineage commitment. GFI1 has oncogenic activity by promoting survival in leukemic T cells and is required for the development and maintenance of T cell leukemia[6,7,8]. In this role, GFI1 antagonizes the p53-dependent induction of apoptosis, in part through regulating post-translational modifications at the C-terminal domain of the p53 protein, and as a consequence through transcriptional regulation of the key apoptotic targets Bax, Bbc[3] (Puma) and Pmaip[1] (Noxa)[8]. Our Gfi[1] KO model features a GFP coding sequence, which is inserted in-frame with the initiation codon of Gfi[1] and replaces exons 3–5 of the Gfi[1] gene, resulting in the production of a GFP transcript under the control of Gfi1’s regulatory sequences and the absence of GFI1 protein[22]

Methods

Results

Conclusion