Abstract
p85α is a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) that is a key lipid enzyme for generating phosphatidylinositol 3, 4, 5-trisphosphate, and subsequently activates signaling that ultimately regulates cell cycle progression, cell growth, cytoskeletal changes, and cell migration. In addition to form a complex with the p110 catalytic subunit, p85α also exists as a monomeric form due to that there is a greater abundance of p85α than p110 in many cell types. Our previous studies have demonstrated that monomeric p85α exerts a pro-apoptotic role in UV response through induction of TNF-α gene expression in PI3K-independent manner. In current studies, we identified a novel biological function of p85α as a positive regulator of epidermal growth factor receptor (EGFR) expression and cell malignant transformation via nucleolin-dependent mechanism. Our results showed that p85α was crucial for EGFR and nucleolin expression and subsequently resulted in an increase of malignant cellular transformation by using both specific knockdown and deletion of p85α in its normal expressed cells. Mechanistic studies revealed that p85α upregulated EGFR protein expression mainly through stabilizing its mRNA, whereas nucleolin (NCL) was able to bind to egfr mRNA and increase its mRNA stability. Consistently, overexpression of NCL in p85α−/− cells restored EGFR mRNA stabilization, protein expression and cell malignant transformation. Moreover, we discovered that p85α upregulated NCL gene transcription via enhancing C-Jun activation. Collectively, our studies demonstrate a novel function of p85α as a positive regulator of EGFR mRNA stability and cell malignant transformation, providing a significant insight into the understanding of biomedical nature of p85α protein in mammalian cells and further supporting that p85α might be a potential target for cancer prevention and therapy.
Highlights
The epidermal growth factor receptor (EGFR), called ErbB1, is first identified member of the subfamily of tyrosine kinase receptors [1]
To define the mechanism underlying p85α regulation of EGFR expression, we first compared EGFR mRNA levels between p85α+/+ and p85α−/− cells, and we found that EGFR mRNA expression was profoundly downregulated in p85α−/− cells as compared with that in p85α+/+ cells (Figure 2A)
EGFR is overexpressed in many aggressive cancers, and previous study indicates that p85α can be activated by transmembrane tyrosine kinase receptors, such as EGFR, HER2 and IGF1-R [41]
Summary
The epidermal growth factor receptor (EGFR), called ErbB1, is first identified member of the subfamily of tyrosine kinase receptors [1]. EGFR plays an important role in extensive crosstalk among multiple signaling pathways and regulation of various cell functions [7]. EGFR plays a significant role in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. EGFR mRNA is central to the flow of genetic information, and regulation of mRNA stability is a powerful mechanism for altering gene expression, and is regulated by multiple proteins [15,16,17]. The monomeric p85α is able to act as a mediator for transducing the insulin-like growth factor 1-dependent cellular response [25] and is involved in the apoptotic response under oxidative stress in a PI3K-independent manner. We reported that p85α was able to regulate EGFR expression by increasing in egfr mRNA stability and EGF-induced cell malignant transformation. We further showed that NCL expression mediated by p85α was able to bind with egfr mRNA, which protected egfr mRNA from degradation
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