title: Overexpression of MYC causes p53-dependent G2 arrest of normal fibroblasts.
abstract: Overexpression of the proto-oncogene MYC has been implicated in the genesis of diverse human cancers. One explanation for the role of MYC in tumorigenesis has been that this gene might drive cells inappropriately through the division cycle, leading to the relentless proliferation characteristic of the neoplastic phenotype. Herein, we report that the overexpression of MYC alone cannot sustain the division cycle of normal cells but instead leads to their arrest in G(2). We used an inducible form of the MYC protein to stimulate normal human and rodent fibroblasts. The stimulated cells passed through G(1) and S but arrested in G(2) and frequently became aneuploid, presumably as a result of inappropriate reinitiation of DNA synthesis. Absence of the tumor suppressor gene p53 or its downstream effector p21 reduced the frequency of both G(2) arrest and aneuploidy, apparently by compromising the G(2) checkpoint control. Thus, relaxation of the G(2) checkpoint may be an essential early event in tumorigenesis by MYC. The loss of p53 function seems to be one mechanism by which this relaxation commonly occurs. These findings dramatize how multiple genetic events can collaborate to produce neoplastic cells.
authors.affiliation: Division of Oncology, Departments of Medicine and Pathology, Stanford University, Stanford, CA 94305-5115, USA. dfelsher@leland.stanford.edu
authors.forename: D W
authors.initials: DW
authors.lastname: Felsher
authors.forename: A
authors.initials: A
authors.lastname: Zetterberg
authors.forename: J
authors.initials: J
authors.lastname: Zhu
authors.forename: T
authors.initials: T
authors.lastname: Tlsty
authors.forename: J M
authors.initials: JM
authors.lastname: Bishop
mesh_terms: D000782:Aneuploidy; D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology; D016195:G2 Phase / Q000235:genetics*; D016259:Genes, myc; D016158:Genes, p53; D006801:Humans; D051379:Mice; D000090063:Proto-Oncogene Mas