The physical interaction of p53 and plakoglobin is necessary for their synergistic inhibition of migration and invasion.

Mahsa Alaee,Vahedah Mehrabani,Amarjot Padda,Manijeh Pasdar,Lucas Churchill

doi:10.18632/oncotarget.8616

Abstract

Plakoglobin (PG) is a paralog of β-catenin with similar adhesive, but contrasting signalling functions. Although β-catenin has well-known oncogenic function, PG generally acts as a tumor/metastasis suppressor by mechanisms that are just beginning to be deciphered. Previously, we showed that PG interacted with wild type (WT) and a number of mutant p53s, and that its tumor/metastasis suppressor activity may be mediated, at least partially, by this interaction. Here, carcinoma cell lines deficient in both p53 and PG (H1299), or expressing mutant p53 in the absence of PG (SCC9), were transfected with expression constructs encoding WT and different fragments and deletions of p53 and PG, individually or in pairs. Transfectants were characterized for their in vitro growth, migratory and invasive properties and for mapping the interacting domain of p53 and PG. We showed that when coexpressed, p53-WT and PG-WT cooperated to decrease growth, and acted synergistically to significantly reduce cell migration and invasion. The DNA-binding domain of p53 and C-terminal domain of PG mediated p53/PG interaction, and furthermore, the C-terminus of PG played a central role in the inhibition of invasion in association with p53.

Highlights

The p53 transcription factor is a tumor suppressor that is absent or mutated in over half of all tumors [1,2,3]. p53 can be activated by various stress signals, including DNA damage, oncogenic insults, hypoxia, loss of cell-cell contact and changes in metabolic behavior
Our results suggested that 1) p53 and PG cooperated to decrease growth whereas they acted synergistically to significantly reduce migration and invasion of H1299 cells, 2) p53/ PG interaction was mediated by the DNA binding (DBD) of p53 and the C-terminus of PG, and 3) the C-terminal domain of PG was necessary for its maximum invasion inhibitory function via interaction with p53
We showed that p53 and PG cooperatively reduced growth and acted synergistically to decrease cellular migration and invasion

Summary

Introduction

The p53 transcription factor is a tumor suppressor that is absent or mutated in over half of all tumors [1,2,3]. p53 can be activated by various stress signals, including DNA damage, oncogenic insults, hypoxia, loss of cell-cell contact and changes in metabolic behavior. P53 activates physiological pathways that regulate cell cycle arrest, DNA repair, apoptosis, autophagy and metabolism [2, 3]. In addition to being a transcriptional regulator, p53 interacts with various cytoplasmic proteins, which mediate its growth regulating activity [4, 5]. The three structural domains [N-terminus (NT), DNA binding (DBD) and C-terminus (CT)] of p53 regulate its cellular functions. The CT contains an oligomerization domain, which allows p53 tetramerization, and a short regulatory domain, which may function as a non-specific DNA binding domain necessary for growth arrest and apoptosis [8, 9]. Flanked by the NT and CT, the DBD confers transcriptional activity on p53 and harbors the majority of p53 mutations [1, 10, 11]. We have identified plakoglobin (PG, γ-catenin) as an endogenous interacting partner of both wild type (WT) and a number of mutant p53s, and have shown that PG’s interaction with these mutants can restore their WT functions [14, 15]

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Conclusion