DN‐R175H p53 mutation is more effective than p53 interference in inducing epithelial disorganization and activation of proliferation signals in human carcinoma cells: Role of E‐cadherin

Abstract

One of the hallmarks of carcinomas is epithelial disorganization, linked to overexpression of matrix metalloproteases (MMP) like MMP-9, loss of intercellular E-cadherin and activation of epidermal growth receptor (EGFR/erbB1). Since the p53 tumor suppressor pathway is inactivated in most human cancers due to gene mutations or defective wt p53 signaling, we now investigated in human wt p53 breast carcinoma MCF-7 cells, whether single treatment with the p53 transactivation pharmacological inhibitor pifithrin-a, transient p53 siRNA interference or stable insertion of a dominant-negative (DN) R175H p53 mutant increase: (i) EGFR/ erbB1 activation, (ii) MMP-9 expression and (iii) loss of surface Ecadherin. Transient abrogation of wt p53 function increased phosphorylation of EGFR/erbB1 and MMP-9 expression. However, all these effects were much more pronounced in cells stably transduced with the dominant negative-Arg-175His mutant p53 (DN-R175H mutant p53), which also showed loss of epithelial cytoarchitecture and extensive E-cadherin downregulation. Collectively, these results support the notion that the DN-R175H mutant p53 exerts a gain of oncogenic function by promoting disruption of E-cadherin intercellular contacts and activation of proliferation signals. Our data suggests that epithelial shape and growth control are unequally affected depending on how wt p53 function is impaired and whether partial or full tumor suppressor activity is lost. ' 2009 UICC

Emerging evidence of epithelial‐to‐mesenchymal transition in lung carcinogenesis

“…A number of genetic alterations—mostly oncogene activation—have shown to induce EMT, each of them either alone, or in combination, with TGF‐β treatment in in vitro cell line models, such as Mardin‐Darby canine kidney cells and mouse models. These genetic changes include mutations of p53 and RAS , and overexpression of c‐Myc , EGFR and HER2 5,40,77–80 . However, one study has indicated that only a minority of cancer cell lines undergo EMT with TGF‐β treatment, 81 suggesting that genetic changes that induce EMT may occur in a context‐dependent manner.…”

<p>Low-Concentration PTX And RSL3 Inhibits Tumor Cell Growth Synergistically By Inducing Ferroptosis In Mutant p53 Hypopharyngeal Squamous Carcinoma</p>

“…Several p53 missense mutations, including those two mutants in our study at codons R248 and R175, are among the most prevalent hotspot mutations in HPSCCs, occurring within the central region of the protein which serves as the p53 DNA-binding domain. [33][34][35][36] They both are localized in the cytoplasm as well where it can exert its "Gain of Function (GOF)" activity. Both mutant types not only lose p53WT'stranscriptional function but also have dominant-negative activity by heterodimerization with p53WT.…”

Plakoglobin restores tumor suppressor activity of p53R175H mutant by sequestering the oncogenic potential of β‐catenin

“…p53 R175H is one of the most common hot spot mutations that are frequently expressed in many cancers . p53 R175H expression has been shown to increase genomic instability, induce oncogenic miRNAs expression and promote cancer stem cell population expansion, epithelial to mesenchymal transition, and drug resistance . p53 R175H mice models show tumor formation and metastasis characteristics of the inherited Li‐Fraumeni syndrome, the disease that is associated with germline mutations in the TP53 gene …”