Epigenetic Down-Regulation of ARF Expression Is a Selection Step in Immortalization of Human Fibroblasts by c-Myc
- 19 November 2007
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Research
- Vol. 5 (11), 1181-1189
- https://doi.org/10.1158/1541-7786.mcr-06-0372
Abstract
The transcription factor c-Myc is implicated in the pathogenesis of many cancers. Among the multiple functions of c-Myc, activation of hTert and other genes involved in cellular life span contributes to its role as an oncogene. However, the ability of c-Myc to directly immortalize human cells remains controversial. We show here that overexpression of c-Myc reproducibly immortalizes freshly isolated human foreskin fibroblasts. c-Myc-immortalized cells displayed no gross karyotypic abnormalities but consisted of an oligoclonal population, suggesting that additional events cooperated to achieve immortalization. Levels of p53 and p16 were increased, but both p53-dependent DNA damage response and growth arrest in response to p16 overexpression remained intact. A marked decrease in expression of the tumor suppressor ARF occurred in several independently established c-Myc-immortalized cell lines. Methylation-specific PCR showed that the ARF gene was methylated in immortalized but not early-passage c-Myc cells, whereas p16 was unmethylated in both cell populations. Restoration of ARF expression by treatment with a demethylating agent or overexpression by a retroviral vector coincided with inhibition of proliferation and senescence of c-Myc-immortalized cells. Our findings predict that epigenetic events play a significant role in human tumors that express high levels of c-Myc.Keywords
Other Versions
This publication has 51 references indexed in Scilit:
- Myc influences global chromatin structureThe EMBO Journal, 2006
- Immortalization of Primary Human Prostate Epithelial Cells by c-MycCancer Research, 2005
- Myc-ARF (Alternate Reading Frame) Interaction Inhibits the Functions of MycPublished by Elsevier BV ,2004
- Myc suppression of the p21Cip1 Cdk inhibitor influences the outcome of the p53 response to DNA damageNature, 2002
- The INK4a/ARF network in tumour suppressionNature Reviews Molecular Cell Biology, 2001
- MYC oncogenes and human neoplastic diseaseOncogene, 1999
- Myc activates telomeraseGenes & Development, 1998
- Extension of Life-Span by Introduction of Telomerase into Normal Human CellsScience, 1998
- Characteristics of an infinite life span diploid human fibroblast cell strain and a near-diploid strain arising from a clone of cells expressing a transfectedv-myc oncogeneExperimental Cell Research, 1991
- Introduction of the activated N-ras oncogene into human fibroblasts by retroviral vector induces morphological transformation and tumorigenicityCarcinogenesis: Integrative Cancer Research, 1990