Activation of Akt/protein kinase B overcomes a G2/M cell cycle checkpoint induced by DNA damage

Eugene S. Kandel, Jennifer Skeen, Nathan Majewski, Antonio Di Cristofano, Pier Paolo Pandolfi, Claudine S. Feliciano, Andrei Gartel, Nissim Hay

Research output: Contribution to journalArticle

232 Citations (Scopus)

Abstract

Activation of Akt, or protein kinase B, is frequently observed in human cancers. Here we report that Akt activation via overexpression of a constitutively active form or via the loss of PTEN can overcome a G2/M cell cycle checkpoint that is induced by DNA damage. Activated Akt also alleviates the reduction in CDC2 activity and mitotic index upon exposure to DNA damage. In addition, we found that PTEN null embryonic stem (ES) cells transit faster from the G2/M to the G1 phase of the cell cycle when compared to wild-type ES cells and that inhibition of phosphoinositol-3-kinase (PI3K) in HEK293 cells elicits G2 arrest that is alleviated by activated Akt. Furthermore, the transition from the G2/M to the G1 phase of the cell cycle in Aktl null mouse embryo fibroblasts (MEFs) is attenuated when compared to that of wild-type MEFs. These results indicate that the PI3K/PTEN/Akt pathway plays a role in the regulation of G2/M transition. Thus, cells expressing activated Akt continue to divide, without being eliminated by apoptosis, in the presence of continuous exposure to mutagen and accumulate mutations, as measured by inactivation of an exogenously expressed herpes simplex virus thymidine kinase (HSV-tk) gene. This phenotype is independent of p53 status and cannot be reproduced by overexpression of Bcl-2 or Myc and Bcl-2 but seems to counteract a cell cycle checkpoint mediated by DNA mismatch repair (MMR). Accordingly, restoration of the G2/M cell cycle checkpoint and apoptosis in MMR-deficient cells, through reintroduction of the missing component of MMR, is alleviated by activated Akt. We suggest that this new activity of Akt in conjunction with its antiapoptotic activity may contribute to genetic instability and could explain its frequent activation in human cancers.

Original languageEnglish (US)
Pages (from-to)7831-7841
Number of pages11
JournalMolecular and Cellular Biology
Volume22
Issue number22
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

Fingerprint

G2 Phase Cell Cycle Checkpoints
Proto-Oncogene Proteins c-akt
DNA Mismatch Repair
DNA Damage
G1 Phase
Embryonic Stem Cells
Cell Cycle
Phosphotransferases
Embryonic Structures
Fibroblasts
Apoptosis
Mitotic Index
Thymidine Kinase
HEK293 Cells
Mutagens
Simplexvirus
Cell Cycle Checkpoints
Neoplasms
Phenotype
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Activation of Akt/protein kinase B overcomes a G2/M cell cycle checkpoint induced by DNA damage. / Kandel, Eugene S.; Skeen, Jennifer; Majewski, Nathan; Di Cristofano, Antonio; Pandolfi, Pier Paolo; Feliciano, Claudine S.; Gartel, Andrei; Hay, Nissim.

In: Molecular and Cellular Biology, Vol. 22, No. 22, 01.11.2002, p. 7831-7841.

Research output: Contribution to journalArticle

Kandel, Eugene S. ; Skeen, Jennifer ; Majewski, Nathan ; Di Cristofano, Antonio ; Pandolfi, Pier Paolo ; Feliciano, Claudine S. ; Gartel, Andrei ; Hay, Nissim. / Activation of Akt/protein kinase B overcomes a G2/M cell cycle checkpoint induced by DNA damage. In: Molecular and Cellular Biology. 2002 ; Vol. 22, No. 22. pp. 7831-7841.
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