A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells.
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 NFkappaBp65 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.
Li
N F
NF
The Centre for Cancer and Inflammation, Institute of Cancer and the Cancer Research-UK Clinical Centre, Barts and The London School of Medicine and Dentistry, London, UK.
Kocher
H M
HM
Salako
M A
MA
Obermueller
E
E
Sandle
J
J
Balkwill
F
F
D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; C509186:TERT protein, human; D019098:Telomerase