Overexpression of MYC causes p53-dependent G(2) arrest of normal fibroblasts

Overexpression of the proto-oncogene MYC has been implicated in the genesis of diverse human cancers. One explanation for the role of MYC in tumorigen esis has been that this gene might drive cells inappropriately through the division cycle, leading to the relentless proliferation characteristic of t he neoplastic phenotype. Herein, we report that the overexpression of MYC a lone 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 stimu late normal human and rodent fibroblasts. The stimulated cells passed throu gh G(1) and S but arrested in G(2) and frequently became aneuploid, presuma bly as a result of inappropriate reinitiation of DNA synthesis. Absence of the tumor suppressor gene p53 or its downstream effector p21 reduced the fr equency 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 see ms to be one mechanism by which this relaxation commonly occurs. These find ings dramatize how multiple genetic events can collaborate to produce neopl astic cells.