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A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells
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A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells
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Journal Article
A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells
2009
Overview
The receptor for macrophage colony-stimulating factor 1 receptor (CSF1R) is a product of the proto-oncogene
c-fms
and a member of the class III transmembrane tyrosine kinase receptor family. Earlier, we described increased mRNA expression of CSF1R in human telomerase reverse transcriptase (hTERT) immortalized human ovarian surface epithelial (IOSE) cell lines derived from a single donor. Here, we further describe that CSF1R is upregulated at both the mRNA and protein level in hTERT immortalized human normal OSE cells from two different donors and in hTERT immortalized human pancreatic ductal epithelial cells. CSF1R was not upregulated in hTERT immortalized epithelial clones that subsequently underwent senescence or in immortalized fibroblasts. Upon stimulation by the CSF1R ligand CSF1, the immortalized epithelial cell lines showed rapid internalization of CSF1R with concomitant down-modulation and colocalization of phosphorylated NFκBp65 with hTERT protein, hTERT translocation into the nucleus and the binding of c-Myc to the hTERT promoter region. Reducing the expression of CSF1R using short hairpin interfering RNA abolished these effects and also decreased cell survival and the number of population doublings under suboptimal culture conditions. The telomerase inhibitor GRN163L confirmed a role for telomerase in the cleavage of the intracellular domain of CSF1R. On the basis of these findings, we suggest that CSF1R may be a critical factor facilitating hTERT immortalization of epithelial cells.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Biological and medical sciences
/ Cancer
/ Cell structures and functions
/ Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes
/ Cell Transformation, Neoplastic - genetics
/ Epithelial Cells - metabolism
/ Epithelial Cells - pathology
/ Fundamental and applied biological sciences. Psychology
/ Gene Expression Regulation, Neoplastic - drug effects
/ Humans
/ Macrophage Colony-Stimulating Factor - pharmacology
/ Medicine
/ Molecular and cellular biology
/ Oncology
/ Receptor, Macrophage Colony-Stimulating Factor - genetics
/ Receptor, Macrophage Colony-Stimulating Factor - metabolism
/ Receptor, Macrophage Colony-Stimulating Factor - physiology
