RRC ID 11011
Author Kitajima S, Miki T, Takegami Y, Kido Y, Noda M, Hara E, Shamma A, Takahashi C.
Title Reversion-inducing cysteine-rich protein with Kazal motifs interferes with epidermal growth factor receptor signaling.
Journal Oncogene
Abstract The reversion-inducing cysteine-rich protein with Kazal motifs (RECK) gene had been isolated as an antagonist to RAS signaling; however, the mechanism of its action is not clear. In this study, the effect of loss of RECK function was assessed in various ways and cell systems. Successive cell cultivation of mouse embryonic fibroblasts (MEFs) according to 3T3 protocol revealed that the germline knockout of RECK confers accelerated cell proliferation and early escape from cellular senescence associated with downregulation of p19(Arf), Trp53 and p21(Cdkn1a). In contrast, short hairpin RNA-mediated depletion of RECK induced irreversible growth arrest along with several features of the Arf, Trp53 and Cdkn1a-dependent cellular senescence. Within 2 days of RECK depletion, we observed a transient increase in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) phosphorylation associated with an upregulated expression of cyclin D1, p19(Arf), Trp53, p21(Cdkn1a) and Sprouty 2. On further cultivation, RAS, AKT and ERK activities were then downregulated to a level lower than control, indicating that RECK depletion leads to a negative feedback to RAS signaling and subsequent cellular senescence. In addition, we observed that epidermal growth factor receptor (EGFR) activity was transiently upregulated by RECK depletion in MEFs, and continuously downregulated by RECK overexpression in colon cancer cells. These findings indicate that RECK is a novel modulator of EGFR signaling.
Volume 30(6)
Pages 737-50
Published 2011-2-10
DOI 10.1038/onc.2010.448
PII onc2010448
PMID 20890302
MeSH Animals Cell Proliferation Cells, Cultured Cellular Senescence / genetics* Colonic Neoplasms / genetics Cyclin D1 / metabolism Cyclin-Dependent Kinase Inhibitor p16 / metabolism Down-Regulation Extracellular Signal-Regulated MAP Kinases / metabolism Fibroblasts / metabolism GPI-Linked Proteins / genetics GPI-Linked Proteins / metabolism* Mice Mice, Inbred C57BL Mice, Knockout Nerve Tissue Proteins / metabolism Proto-Oncogene Proteins c-akt / metabolism RNA, Small Interfering / metabolism Receptor, Epidermal Growth Factor / metabolism* Signal Transduction Tumor Suppressor Protein p53 / metabolism p21-Activated Kinases / metabolism
IF 6.854
Times Cited 13
WOS Category GENETICS & HEREDITY ONCOLOGY BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
Human and Animal Cells MC3T3-G2/PA6 (RCB1127)