Title: The N-terminal region of p27 inhibits HIF-1α protein translation in ribosomal protein S6-dependent manner by regulating PHLPP-Ras-ERK-p90RSK axis.
Authors: Zhang, D; Liu, J; Mi, X; Liang, Y; Li, J; Huang, C
Published In Cell Death Dis, (2014)
Abstract: P27 was identified as a tumor suppressor nearly two decades, being implicated in cell-cycle control, differentiation, senescence, apoptosis and motility. Our present study, for the first time to the best of our knowledge, revealed a potential role of p27 in inhibiting S6-mediated hypoxia-inducible factor-1α (HIF-1α) protein translation, which contributed to the protection from environmental carcinogen (sodium arsenite)-induced cell transformation. Our findings showed that depletion of p27 expression by knockout and knockdown approaches efficiently enhanced S6 phosphorylation in arsenite response via overactivating Ras/Raf/MEK/ERK pathway, which consequently resulted in the stimulation of p90RSK (90 kDa ribosomal S6 kinase), a direct kinase for S6 phosphorylation. Although PI3K/AKT pathway was also involved in S6 activation, blocking AKT and p70S6K activation did not attenuate arsenite-induced S6 activation in p27-/- cells, suggesting p27 specifically targeted Ras/ERK pathway rather than PI3K/AKT pathway for inhibition of S6 activation in response to arsenite exposure. Further functional studies found that p27 had a negative role in cell transformation induced by chronic low-dose arsentie exposure. Mechanistic investigations showed that HIF-1α translation was upregulated in p27-deficient cells in an S6 phosphorylation-dependent manner and functioned as a driving force in arsenite-induced cell transformation. Knockdown of HIF-1α efficiently reversed arsenite-induced cell transformation in p27-depleted cells. Taken together, our findings provided strong evidence showing that by targeting Ras/ERK pathway, p27 provided a negative control over HIF-1α protein synthesis in an S6-dependent manner, and abrogated arsenite-induced cell transformation via downregulation of HIF-1α translation.
PubMed ID: 25412313
MeSH Terms: Animals; Arsenites/toxicity; Carcinogens/toxicity; Cell Line; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Cell Transformation, Neoplastic/pathology; Cyclin-Dependent Kinase Inhibitor p27/genetics*; Cyclin-Dependent Kinase Inhibitor p27/metabolism; Epithelial Cells/cytology; Epithelial Cells/drug effects; Epithelial Cells/metabolism; Extracellular Signal-Regulated MAP Kinases/genetics*; Extracellular Signal-Regulated MAP Kinases/metabolism; Fibroblasts/cytology; Fibroblasts/drug effects; Fibroblasts/metabolism; Gene Expression Regulation; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit/genetics*; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism; Mice; NIH 3T3 Cells; Nuclear Proteins/genetics*; Nuclear Proteins/metabolism; Phosphoprotein Phosphatases/genetics*; Phosphoprotein Phosphatases/metabolism; Protein Biosynthesis; Protein Structure, Tertiary; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Ribosomal Protein S6 Kinases, 90-kDa/genetics*; Ribosomal Protein S6 Kinases, 90-kDa/metabolism; Ribosomal Protein S6 Kinases/genetics*; Ribosomal Protein S6 Kinases/metabolism; Signal Transduction; Sodium Compounds/toxicity; ras Proteins/genetics*; ras Proteins/metabolism