title: p85α promotes nucleolin transcription and subsequently enhances EGFR mRNA stability and EGF-induced malignant cellular transformation.
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.
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Qipeng
authors.initials: Q
authors.lastname: Xie
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Xirui
authors.initials: X
authors.lastname: Guo
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Jiayan
authors.initials: J
authors.lastname: Gu
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Honglei
authors.initials: H
authors.lastname: Jin
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Haishan
authors.initials: H
authors.lastname: Huang
authors.affiliation: Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Jingxia
authors.initials: J
authors.lastname: Li
authors.affiliation: Zhejiang Provincial Key Laboratory for Technology and Application of Model Organisms, School of Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.|Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, NY 10987, USA.
authors.forename: Chuanshu
authors.initials: C
authors.lastname: Huang
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D002478:Cells, Cultured; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D015151:Immunoblotting; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020871:RNA Stability / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D000097796:Nucleolin
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C512478:EGFR protein, human
keywords: EGFR; PI3K; cell transformation; nucleolin; p85α