P85? promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation.

ABSTRACT: p85? 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, p85? also exists as a monomeric form due to that there is a greater abundance of p85? than p110 in many cell types. Our previous studies have demonstrated that monomeric p85? exerts a pro-apoptotic role in UV response through induction of TNF-? gene expression in PI3K-independent manner. In current studies, we identified a novel biological function of p85? as a positive regulator of epidermal growth factor receptor (EGFR) expression and cell malignant transformation via nucleolin-dependent mechanism. Our results showed that p85? 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 p85? in its normal expressed cells. Mechanistic studies revealed that p85? 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 p85?-/- cells restored EGFR mRNA stabilization, protein expression and cell malignant transformation. Moreover, we discovered that p85? upregulated NCL gene transcription via enhancing C-Jun activation. Collectively, our studies demonstrate a novel function of p85? as a positive regulator of EGFR mRNA stability and cell malignant transformation, providing a significant insight into the understanding of biomedical nature of p85? protein in mammalian cells and further supporting that p85? might be a potential target for cancer prevention and therapy.

SUBMITTER: Xie Q 

PROVIDER: S-EPMC4941340 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other