p32 is a negative regulator of p53 tetramerization and transactivation

Abstract

p53 is a sequence‐specific transcription factor, and proper regulation of p53 transcriptional activity is critical for orchestrating different tumor‐suppressive mechanisms. p32 is a multifunctional protein which interacts with a large number of viral proteins and transcription factors. Here, we investigate the effect of p32 on p53 transactivation and identify a novel mechanism by which p32 alters the functional characteristics of p53. Specifically, p32 attenuates p53‐dependent transcription through impairment of p53 binding to its response elements on target genes. Upon p32 expression, p53 levels bound at target genes are decreased, and p53 target genes are inactivated, strongly indicating that p32 restricts p53 occupancy and function at target genes. The primary mechanism contributing to the observed action of p32 is the ability of p32 to interact with the p53 tetramerization domain and to block p53 tetramerization, which in turn enhances nuclear export and degradation of p53, leading to defective p53 transactivation. Collectively, these data establish p32 as a negative regulator of p53 function and suggest the therapeutic potential of targeting p32 for cancer treatment.

Overexpression of Multifunctional Protein p32 Promotes a Malignant Phenotype in Colorectal Cancer Cells

“…Interestingly, these functions are closely related to the intracellular localization of p32 in colon cancer cells. Although p32 is a protein that is located primarily at the mitochondria, it has also been found located at the plasma membrane and at the nucleus by multiple authors (13,14,37). The PI3K/AKT pathway and Ras/ERK signaling pathways are frequently dysregulated in colon cancer.…”

“…The protein has a mitochondrial localization signal at its N-terminus (12). However, multiple studies have shown that depending on the cell context, the mature variant is not only found in the mitochondrial matrix but can also be found in the nucleus (13,14) as well as on the cell surface (15)(16)(17)(18). Due to this, p32 is considered as a multicompartmental protein (15).…”

“…In addition, one of the most important features of p32 is the ability to bind multiple unrelated ligands at each of the subcellular localization where it is found. Among the most important ligands are included: serum proteins as C1q, Hkininogen (HK) and fibrinogen; extracellular matrix components as hyaluronic acid; multiple viral and bacterial proteins; mitochondrial proteins as short mitochondrial ARF (smARF), cytochrome B2 and HRK; cytosol proteins as PKC and nuclear proteins as pre-mRNA splicing factor (SF2/ASF), Lamin B receptor and p53 (14,19,20). Precisely because it is a multicompartmental, multiligand, and highly flexible protein (21), it has been assigned many diverse functions in each of its subcellular locations.…”

Evolution-guided mutagenesis of the cytoplasmic incompatibility proteins: Identifying CifA’s complex functional repertoire and new essential regions in CifB

“…Moreover, pum in spermatogenesis negatively regulates the expression of p53 which is involved in DNA repair and apoptosis, increases apoptosis, and reduces sperm production and fertility [ 62 ]. Intriguingly, mitochondrial protein p32 is a candidate suppressor of CI based on in vitro pull-down assays using Drosophila lysates, and p32 regulates p53 activation [ 63 ], suggesting that pum in spermatogenesis may influence similar pathways in CI. Additionally, Wolbachia infection has been shown to have a considerable impact on the fly transcriptome including sRNA profiles [ 64 – 66 ].…”

The guardian's choice: how p53 enables context‐specific decision‐making in individual cells

“…(encoded by C1QBP) was shown to interfere with p53's tetramerization [95]. This way, p32 inhibits DNA binding, occupancy at target genes and p53 dependent transcription.…”