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

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.

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

“…Molecular chaperones are a diverse group of proteins crucial for maintaining protein homeostasis and protecting cells against stress 1 . Improper function of these essential machines can lead to the accumulation of misfolded and aggregated proteins, which have been correlated with a wide array of human disorders, including neurodegeneration, myopathies, and cancer [2][3][4][5] .…”

Prognostic model and immunotherapy prediction based on molecular chaperone-related lncRNAs in lung adenocarcinoma

“…In addition, drugs targeting molecular chaperone-related genes are also widely used in clinical practice. chaperones-related related genes with great clinical potential, such as HSP90 and P53, making immunotherapy become an important means of tumor treatment ( Armstrong et al, 2018 ; Kaida and Iwakuma, 2021 ). Although molecular chaperones can be used as prognostic indicators in patients with LUAD, the utility of using only a single biomarker is limited.…”

Transcriptomic profiles of the ruminal wall in Italian Mediterranean dairy buffaloes fed green forage

“…Particularly notable was up-regulation of genes whose products counteract stressful conditions, such as NUDT18 , DNAJA4 and HSF4 genes. NUDT18 catalyzes the hydrolysis of 8-oxo-dGTP - one of the best characterized DNA damages caused by oxidative stress - to produce the monophosphate form 8-oxo-dGMP (odGMP), which is unusable for DNA synthesis, thus preserving cells from oxidation-mediated mutations [ 63 ]; DNAJA4 belongs to the family of heat shock proteins HSP40, which cooperate with HSP70 chaperones to counteract protein misfolding and aggregation in stress conditions [ 64 ]; HSF4 gene encodes a factor that modulates the expression of heat shock proteins under stressful conditions [ 65 ] and exerts a protective effect against oxidative stress [ 66 ]. These findings suggest that green feed may exert an anti-oxidant function, by positively modulating factors that counteract stressful stimuli.…”