Regulation of p53 and Cancer Signaling by Heat Shock Protein 40/J-Domain Protein Family Members.

Atsushi Kaida,Tomoo Iwakuma

doi:10.3390/ijms222413527

Abstract

Heat shock proteins (HSPs) are molecular chaperones that assist diverse cellular activities including protein folding, intracellular transportation, assembly or disassembly of protein complexes, and stabilization or degradation of misfolded or aggregated proteins. HSP40, also known as J-domain proteins (JDPs), is the largest family with over fifty members and contains highly conserved J domains responsible for binding to HSP70 and stimulation of the ATPase activity as a co-chaperone. Tumor suppressor p53 (p53), the most frequently mutated gene in human cancers, is one of the proteins that functionally interact with HSP40/JDPs. The majority of p53 mutations are missense mutations, resulting in acquirement of unexpected oncogenic activities, referred to as gain of function (GOF), in addition to loss of the tumor suppressive function. Moreover, stability and levels of wild-type p53 (wtp53) and mutant p53 (mutp53) are crucial for their tumor suppressive and oncogenic activities, respectively. However, the regulatory mechanisms of wtp53 and mutp53 are not fully understood. Accumulating reports demonstrate regulation of wtp53 and mutp53 levels and/or activities by HSP40/JDPs. Here, we summarize updated knowledge related to the link of HSP40/JDPs with p53 and cancer signaling to improve our understanding of the regulation of tumor suppressive wtp53 and oncogenic mutp53 GOF activities.

Highlights

Tumor suppressor p53 (p53) is a transcription factor that regulates the expression of genes involved in cell cycle arrest and apoptosis, thereby functioning as a tumor suppressor [1,2]
While p53 protein mainly localizes to the nucleus, p53 is detected in the cytoplasm, endoplasmic reticulum (ER), and mitochondria, thereby contributing to a variety of cellular activities [8,9,10,11,12]
We have given an overview of HSP40/J-domain proteins (JDPs) mainly by focusing on their roles in cancer signaling and p53 functions (Figure 2 and Table 1)

Summary

Introduction

Tumor suppressor p53 (p53) is a transcription factor that regulates the expression of genes involved in cell cycle arrest and apoptosis, thereby functioning as a tumor suppressor [1,2]. The same group shows that DNAJB9/MDG1/ERdj overexpression inhibits the H-RASV12-induced p53-dependent senescence in MEFs and promotes the cellular transformation [73] In support of these findings, in human non-gestational choriocarcinoma samples, two missense mutations in the DNAJB9/MDG1/ERdj gene are found (F46Y, H47R), while the introduction of site-specific mutations in the DNAJB9/MDG1/ERdj gene in gestational choriocarcinoma JEG-3 cells results in reduced DNAJB9/MDG1/ERdj mRNA and protein levels with increase in the wtp levels [74]. These studies suggest the tumor-promoting function of DNAJB9/MDG1/ERdj by inhibiting wtp, which is distinct from the aforementioned tumor-suppressive function of DNAJB9/MDG1/ERdj in breast cancer by Kim et al [144]. The roles of DNAJB9/MDG1/ERdj in cancer suppression or progression could be dependent on the presence of wtp in cells or other cellular contexts

Other DNAJB Members and Cancer

DNAJC9

Other DNAJC Members and Cancer

Discussion

Conclusions