Role of Stat3 in Regulating p53 Expression and Function

Abstract

Loss of p53 function by mutation is common in cancer. However, most natural p53 mutations occur at a late stage in tumor development, and many clinically detectable cancers have reduced p53 expression but no p53 mutations. It remains to be fully determined what mechanisms disable p53 during malignant initiation and in cancers without mutations that directly affect p53. We show here that oncogenic signaling pathways inhibit the p53 gene transcription rate through a mechanism involving Stat3, which binds to the p53 promoter in vitro and in vivo. Site-specific mutation of a Stat3 DNA-binding site in the p53 promoter partially abrogates Stat3-induced inhibition. Stat3 activity also influences p53 response genes and affects UV-induced cell growth arrest in normal cells. Furthermore, blocking Stat3 in cancer cells up-regulates expression of p53, leading to p53-mediated tumor cell apoptosis. As a point of convergence for many oncogenic signaling pathways, Stat3 is constitutively activated at high frequency in a wide diversity of cancers and is a promising molecular target for cancer therapy. Thus, repression of p53 expression by Stat3 is likely to have an important role in development of tumors, and targeting Stat3 represents a novel therapeutic approach for p53 reactivation in many cancers lacking p53 mutations.The p53 protein is a potent inhibitor of cell growth, arresting cell cycle progression at several points and inducing apoptosis of cells undergoing uncontrolled growth (23,24). It has been well documented that the Ras and Myc oncogenes activate p53 by inhibiting degradation of p53 protein and that transformation by these oncogenes requires mutation of p53 itself or silencing of ARF expression in cultured cells and animal models (19,22). The critical role of p53 as an important tumor suppressor is further underscored by the fact that p53 is the most commonly altered gene in cancer. However, p53 mutation is often a late event in malignant progression (2), and many clinically detectable cancers without p53 mutations exhibit reduced p53 expression (33,36). In breast cancer, for example, 80% of the tumors do not have p53 mutations and a 5-to 10-fold reduction of the p53 mRNA level is found in tumor relative to normal breast cells and tissues (36). These observations indicate the importance of mechanisms to either block p53 activity or silence p53 expression during malignant initiation and progression. Indeed, it has been shown that the oncogenic potential of simian virus 40 (SV40) large T antigen depends on its ability to negatively regulate p53 activity, providing a mechanism by which oncoproteins inhibit p53 function in the absence of p53 mutations (3,16,34,38). Moreover, lack of HOX5A, a p53 transcription activator, has been shown to contribute to the inhibition of p53 expression in breast cancer (36).Several recent studies have reported that the c-Src tyrosine kinase opposes p53 activity during platelet-derived growth factor (PDGF)-induced mitogenesis (7,18). Because the requirement for c-Src in PDGF receptor (P...

ATF3 Activates Stat3 Phosphorylation through Inhibition of p53 Expression in Skin Cancer Cells

“…Consistently, DNA binding activity of Stat3 is regulated by p53 in human prostate cancer cells (Lin et al, 2002), and ATF3 and Stat3 synergistically modulate neuronal injury-inducible gene expression. Reversely, Stat3 could regulate p53 expression and function (Niu et al, 2005). These reports are coordinated with our findings that ATF3-p53-Stat3 signaling cascade indeed regulates skin cancer cell proliferation (Kiryu-Seo et al, 2008).…”

Mutant p53 (G199V) Gains Antiapoptotic Function through Signal Transducer and Activator of Transcription 3 in Anaplastic Thyroid Cancer Cells

“…Thus, either blocking of p53 activity or silencing of p53 expression is likely to have an important role in the initiation and progression of tumorigenesis. A previous study showed that constitutively activated STAT3 inhibits the ability of endogenous p53 to regulate p53-responsive genes, indicating that repression of p53 by STAT3 is likely to have an important role in tumorigenesis as well (38). Irrespective of those studies on the cross talk between mt p53 and the STAT3 pathway, it has not been elucidated to date that mt p53 gains an antiapoptotic function through STAT3.…”

Dietary compounds as potent inhibitors of the signal transducers and activators of transcription (STAT) 3 regulatory network

“…Phosphorylation of STAT factors leading to their dimerization (5). As a to the p53 promoter (Niu et al 2005). In addition, recent studies have shown that activation of the STAT3 gene leads to the overexpression of AKT, a key target of phosphatidylinositol 3-kinase (PI3K) that is constitutively activated in acute myeloid leukemia (AML).…”