A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells
Open Access
- 10 November 2008
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 28 (5), 773-780
- https://doi.org/10.1038/onc.2008.412
Abstract
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.Keywords
This publication has 15 references indexed in Scilit:
- Human ovarian surface epithelial cells immortalized with hTERT maintain functional pRb and p53 expressionCell Proliferation, 2007
- Lipid modification of GRN163, an N3′ → P5′ thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibitionOncogene, 2005
- A modified medium that significantly improves the growth of human normal ovarian surface epithelial (OSE) cells in vitroLaboratory Investigation, 2004
- Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotypeNature Genetics, 1999
- Absence of cancer–associated changes in human fibroblasts immortalized with telomeraseNature Genetics, 1999
- Growth and differentiation signals regulated by the M-CSF receptorMolecular Reproduction and Development, 1997
- Anti-Colony-Stimulating Factor-1 Antibody Staining in Primary Breast Adenocarcinomas Correlates With Marked Inflammatory Cell Infiltrates and PrognosisJNCI Journal of the National Cancer Institute, 1994
- The cytokine CSF-1 (M-CSF) expressed by endometrial carcinomas in vivo and in vitro, may also be a circulating tumor marker of neoplastic disease activity in endometrial carcinoma patientsInternational Journal of Radiation Oncology*Biology*Physics, 1990
- Circulating levels of CSF-1 (M-CSF) a lymphohematopoietic cytokine may be a useful marker of disease status in patients with malignant ovarian neoplasmsInternational Journal of Radiation Oncology*Biology*Physics, 1989
- High level expression of fms proto-oncogene mRNA is observed in clinically aggressive human endometrial adenocarcinomasInternational Journal of Radiation Oncology*Biology*Physics, 1988