"Overexpression of MYC Causes p53-Dependent G₂ Arrest of Normal Fibroblasts". 

Dean W. Felsher *,¹, Anders Zetterberg ³, Jiyue Zhu ⁴, Thea Tlsty ², and J. Michael Bishop ⁴

¹Division of Oncology, Depts. of Medicine and Pathology, Stanford University, Stanford, CA 94305-5115; ²Department of Pathology, University of California, San Francisco, CA 94143-0506;
³ Department of Oncology-Pathology, Cancer Center Karolinksa, Stockholm, Sweden CCK R8:04; and
⁴G. W. Hooper Foundation, and the Dept. of Microbiology and Immunology, University of California, San Francisco, CA 94143-0552
^* To whom reprint requests should be addressed. E-mail: dfelsher@leland.stanford.edu.

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 mightdrive cells inappropriately through the division cycle, leadingto the relentless proliferation characteristic of the neoplasticphenotype. Herein, we report that the overexpression of MYC alone cannot sustain the division cycle of normal cells but instead leads to their arrest in G₂. We used an inducible form of the MYC protein to stimulate normal human and rodent fibroblasts. The stimulated cells passed through G₁ and S but arrested in G₂ 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 G₂ arrest and aneuploidy, apparently by compromising theG₂ checkpoint control. Thus, relaxation of the G₂ 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.

^* To whom reprint requests should be addressed. E-mail: dfelsher@leland.stanford.edu.

1. "Mated Models of Gene Regulation within Eukaryotes".

2. "Oncogenes as Molecular Targets within Active Chromatin".