Overexpression of MYC causes p53-dependent G2 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 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.

[1]  Goberdhan P Dimri,et al.  Regulation of a Senescence Checkpoint Response by the E2F1 Transcription Factor and p14ARF Tumor Suppressor , 2000, Molecular and Cellular Biology.

[2]  M. Roussel,et al.  Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. , 1999, Genes & development.

[3]  C. Dang,et al.  c-Myc Overexpression Uncouples DNA Replication from Mitosis , 1999, Molecular and Cellular Biology.

[4]  G. Evan,et al.  Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. , 1999, Molecular cell.

[5]  D. Felsher,et al.  Transient excess of MYC activity can elicit genomic instability and tumorigenesis. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[6]  L. Chin,et al.  Telomerase reverse transcriptase gene is a direct target of c-Myc but is not functionally equivalent in cellular transformation , 1999, Oncogene.

[7]  R. Dalla‐Favera,et al.  Direct activation of TERT transcription by c-MYC , 1999, Nature Genetics.

[8]  K. Kinzler,et al.  Requirement for p53 and p21 to sustain G2 arrest after DNA damage. , 1998, Science.

[9]  S. Lowe,et al.  Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. , 1998, Genes & development.

[10]  D. Woods,et al.  Senescence of human fibroblasts induced by oncogenic Raf. , 1998, Genes & development.

[11]  C. Sherr,et al.  Tumor surveillance via the ARF-p53 pathway. , 1998, Genes & development.

[12]  J L Cleveland,et al.  Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. , 1998, Genes & development.

[13]  G. Hannon,et al.  Myc activates telomerase. , 1998, Genes & development.

[14]  T. Jacks,et al.  Characterization of the p53-Dependent Postmitotic Checkpoint following Spindle Disruption , 1998, Molecular and Cellular Biology.

[15]  G. Stark,et al.  MYC Abrogates p53-Mediated Cell Cycle Arrest in N-(Phosphonacetyl)-l-Aspartate-Treated Cells, Permitting CAD Gene Amplification , 1998, Molecular and Cellular Biology.

[16]  G. Wahl,et al.  DNA rereplication in the presence of mitotic spindle inhibitors in human and mouse fibroblasts lacking either p53 or pRb function. , 1997, Cancer research.

[17]  S. Lowe,et al.  Oncogenic ras Provokes Premature Cell Senescence Associated with Accumulation of p53 and p16INK4a , 1997, Cell.

[18]  Amanda G Paulovich,et al.  When Checkpoints Fail , 1997, Cell.

[19]  A. Levine p53, the Cellular Gatekeeper for Growth and Division , 1997, Cell.

[20]  S. Mai,et al.  c-Myc overexpression associated DHFR gene amplification in hamster, rat, mouse and human cell lines. , 1996, Oncogene.

[21]  L. Donehower,et al.  Synergy between a human c-myc transgene and p53 null genotype in murine thymic lymphomas: contrasting effects of homozygous and heterozygous p53 loss. , 1995, Oncogene.

[22]  G. Evan,et al.  Oncogenes and cell death. , 1994, Current opinion in genetics & development.

[23]  A. Zetterberg,et al.  A cell cycle study of human mammary epithelial cells. , 1993, Cell biology international.

[24]  Didier Picard,et al.  Chimaeras of Myc oncoprotein and steroid receptors cause hormone-dependent transformation of cells , 1989, Nature.

[25]  M. Henriksson,et al.  Proteins of the Myc network: essential regulators of cell growth and differentiation. , 1996, Advances in cancer research.

[26]  A. Patel,et al.  myc function and regulation. , 1992, Annual review of biochemistry.

[27]  C. Cerni,et al.  c-myc and functionally related oncogenes induce both high rates of sister chromatid exchange and abnormal karyotypes in rat fibroblasts. , 1986, Current topics in microbiology and immunology.