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PMID:10962037

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Citation

Felsher, DW, Zetterberg, A, Zhu, J, Tlsty, T and Bishop, JM (2000) Overexpression of MYC causes p53-dependent G2 arrest of normal fibroblasts. Proc. Natl. Acad. Sci. U.S.A. 97:10544-8

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.

Links

PubMed PMC27061 Online version:10.1073/pnas.190327097

Keywords

Aneuploidy; Animals; Cell Division; Cells, Cultured; Fibroblasts/cytology; G2 Phase/genetics; Genes, myc; Genes, p53; Humans; Mice

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MYC

involved_in

GO:0051782: negative regulation of cell division

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002620)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:1902255: positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:P53

acts_upstream_of_negative_effect

GO:1902749: regulation of cell cycle G2/M phase transition

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:P53

involved_in

GO:0007050: cell cycle arrest

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:P53

involved_in

GO:0048147: negative regulation of fibroblast proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0051782: negative regulation of cell division

ECO:0000314: direct assay evidence used in manual assertion

P

occurs_in:(CL:0002620)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0051276: chromosome organization

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0048147: negative regulation of fibroblast proliferation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0007050: cell cycle arrest

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002620)
  • happens_during:(GO:0000085)

Seeded From UniProt

complete

HUMAN:MYC

involved_in

GO:0044346: fibroblast apoptotic process

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete


See also

References

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