title: Gene expression signature of c-MYC-immortalized human fibroblasts reveals loss of growth inhibitory response to TGFβ.
abstract: Cancer cells exhibit the ability to proliferate indefinitely, but paradoxically, overexpression of cellular oncogenes in primary cells can result in a rapid and irreversible cell cycle arrest known as oncogene-induced senescence (OIS). However, we have shown that constitutive overexpression of the oncogene c-MYC in primary human foreskin fibroblasts results in a population of cells with unlimited lifespan; these immortalized cells are henceforth referred to as iMYC. Here, in order to further elucidate the mechanisms underlying the immortalization process, a gene expression signature of three independently established iMYC cell lines compared to matched early passage c-MYC overexpressing cells was derived. Network analysis of this "iMYC signature" indicated that a large fraction of the down-regulated genes were functionally connected and major nodes centered around the TGFβ, IL-6 and IGF-1 signaling pathways. Here, we focused on the functional validation of the alteration of TGFβ response during c-MYC-mediated immortalization. The results demonstrate loss of sensitivity of iMYC cells to activation of TGFβ signaling upon ligand addition. Furthermore, we show that aberrant regulation of the p27 tumor suppressor protein in iMYC cells is a key event that contributes to loss of response to TGFβ. These findings highlight the potential to reveal key pathways contributing to the self-renewal of cancer cells through functional mining of the unique gene expression signature of cells immortalized by c-MYC.
authors: Program in Cancer Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors: Myra L
authors: ML
authors: Wang
authors: Ryan
authors: R
authors: Walsh
authors: Kristin L
authors: KL
authors: Robinson
authors: Julja
authors: J
authors: Burchard
authors: Steven R
authors: SR
authors: Bartz
authors: Michele
authors: M
authors: Cleary
authors: Denise A
authors: DA
authors: Galloway
authors: Carla
authors: C
authors: Grandori
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D016271:Proto-Oncogene Proteins c-myc; D016212:Transforming Growth Factor beta; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007334:Insulin-Like Growth Factor I