Expression profiling identifies three pathways altered in cellular immortalization: interferon, cell cycle, and cytoskeleton.
Abrogation of cellular senescence, resulting in immortalization, is a necessary step in the tumorigenic transformation of a cell. Four independent, spontaneously immortalized Li-Fraumeni syndrome (LFS) cell lines were used to analyze the gene expression changes that may have given these cell lines the growth advantage required to become immortal. A cellular senescence-like phenotype can be induced in immortal LFS cells by treating them with the DNA methyltransferase (DNMT) inhibitor 5-aza-deoxycytidine. We hypothesized, therefore, that genes epigenetically silenced by promoter methylation are potentially key regulators of senescence. We used microarrays to compare the epigenetic gene expression profiles of precrisis LFS cells with immortal LFS cells. Gene ontology analysis of the expression data revealed a statistically significant contribution of interferon pathway, cell cycle, and cytoskeletal genes in the process of immortalization. The identification of the genes and pathways regulating immortalization will lead to a better understanding of cellular immortalization and molecular targets in cancer and aging.
Fridman
Aviva Levine
AL
Program in Molecular Biology and Human Genetics, Barbara Ann Karmanos Cancer Institute, and Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, 110 East Warren Ave., Detroit, Michigan 48201, USA.
Tang
Lin
L
Kulaeva
Olga I
OI
Ye
Bin
B
Li
Qunfang
Q
Nahhas
Fatimah
F
Roberts
Paul C
PC
Land
Susan J
SJ
Abrams
Judith
J
Tainsky
Michael A
MA
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D003599:Cytoskeleton / Q000235:genetics; D019175:DNA Methylation; D000077209:Decitabine; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D016158:Genes, p53; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D016899:Interferon-beta / Q000378:metabolism; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; D016899:Interferon-beta; D000077209:Decitabine; D001374:Azacitidine