title: How to become immortal: let MEFs count the ways.
abstract: Understanding the molecular mechanisms and biological consequences of genetic changes occurring during bypass of cellular senescence spans a broad area of medical research from the cancer field to regenerative medicine. Senescence escape and immortalisation have been intensively studied in murine embryonic fibroblasts as a model system, and are known to occur when the p53/ARF tumour suppressor pathway is disrupted. We showed recently that murine fibroblasts with a humanised p53 gene (Hupki cells, from a human p53 knock-in mouse model) first senesce, and then become immortalised in the same way as their homologues with normal murine p53. In both cell types, immortalised cultures frequently sustain either a p53 gene mutation matching a human tumour mutation and resulting in loss of p53 transcriptional transactivation, or a biallelic deletion at the p19/ARF locus. Whilst these genetic events were not unexpected, we were surprised to find that a significant proportion of immortalised cell cultures apparently had neither a p53 mutation nor loss of p19/ARF. Here we consider various routes to p53/ARF disruption in senescence bypass, and dysfunction of other tumour suppressor networks that may contribute to release from tenacious cell cycle arrest in senescent cultures.
authors.affiliation: Faculty of Medicine and Health, University of Leeds, LIGHT Laboratories, Leeds, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Odell
authors.forename: Jon
authors.initials: J
authors.lastname: Askham
authors.forename: Catherine
authors.initials: C
authors.lastname: Whibley
authors.forename: Monica
authors.initials: M
authors.lastname: Hollstein
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D002460:Cell Line; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D016158:Genes, p53; D006801:Humans; D051379:Mice; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53