Negative regulation of dE2F1 by cyclin-dependent kinases controls cell cycle timing.
Many types of cells compensate for induced alterations in the length of one cell cycle phase (G1, S, or G2) by altering the lengths of the other phases. Here we show that, when cells in Drosophila wing discs are delayed in G1, they maintain normal division rates by accelerating passage through S and G2. Similarly, when G2-->M progression is retarded, G1-->S progression accelerates. This compensation mechanism employs negative feedback in which the cyclin-dependent kinases Cdk1 and Cdk2 downregulate the transcription factor dE2F1. dE2F1, in turn, positively regulates cyclin E and string/cdc25, which activate the Cdks to drive cell cycle progression. This homeostatic mechanism coordinates rates of G1-->S and G2-->M progression, maintaining normal rates of proliferation when cell cycle controls are perturbed (e.g., by ectopic Dacapo, dWee1, dMyc, or Rheb). Without dE2F1, the compensatory mechanism fails, and treatments that alter Cdk activity cause aberrant cell cycle timing and cell death.
Reis
Tânia
T
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
Edgar
Bruce A
BA
D000818:Animals; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D015536:Down-Regulation / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D050684:E2F Transcription Factors; D025461:Feedback, Physiological / Q000235:genetics / Q000502:physiology*; D016193:G1 Phase / Q000235:genetics; D016195:G2 Phase / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014921:Wings, Animal / Q000166:cytology / Q000254:growth & development / Q000378:metabolism
D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D014157:Transcription Factors; D018844:Cyclin-Dependent Kinases; D017027:Protein Tyrosine Phosphatases; C059217:stg protein, Drosophila