A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo.
Terminally differentiated cells in Drosophila melanogaster wings and eyes are largely resistant to proliferation upon deregulation of either E2F or cyclin E (CycE), but exogenous expression of both factors together can bypass cell cycle exit. In this study, we show this is the result of cooperation of cell cycle control mechanisms that limit E2F-CycE positive feedback and prevent cycling after terminal differentiation. Aberrant CycE activity after differentiation leads to the degradation of E2F activator complexes, which increases the proportion of CycE-resistant E2F repressor complexes, resulting in stable E2F target gene repression. If E2F-dependent repression is lost after differentiation, high anaphase-promoting complex/cyclosome (APC/C) activity degrades key E2F targets to limit cell cycle reentry. Providing both CycE and E2F activities bypasses exit by simultaneously inhibiting the APC/C and inducing a group of E2F target genes essential for cell cycle reentry after differentiation. These mechanisms are essential for proper development, as evading them leads to tissue outgrowths composed of dividing but terminally differentiated cells.
Buttitta
Laura A
LA
Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. lbuttitt@fhcrc.org
Katzaroff
Alexia J
AJ
Edgar
Bruce A
BA
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000033:anatomy & histology / Q000502:physiology; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020411:Oligonucleotide Array Sequence Analysis; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism; D014921:Wings, Animal / Q000033:anatomy & histology / Q000502:physiology
D018797:Cell Cycle Proteins; D019927:Cyclin E; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; D011993:Recombinant Fusion Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D051357:Cyclin-Dependent Kinase 2; C495887:cdk2 protein, Drosophila; D017027:Protein Tyrosine Phosphatases; C059217:stg protein, Drosophila