Developmental control of cell cycle exit

Summary

Principal Investigator: LINDA BREEDEN
Abstract: An unsolved mystery of development concerns how growth and form are controlled. The regulation of cell proliferation is central to this problem, and the mechanisms controlling cell cycle arrest upon cell differentiation are particularly relevant. Cell cycle exit is also critical in carcinogenesis, where it is bypassed, and in wound healing and regeneration, where it is reversed to allow renewed proliferation. While cell cycle exit has been studied in cell culture and in vivo in several model organisms, the mechanisms that couple differentiation signals to the cell cycle control apparatus remain poorly understood. No general paradigm exists explaining the ubiquitous coupling of cell differentiation to G1 arrest. This proposal is to study cell cycle exit at differentiation in Drosophila in three well-characterized contexts: the embryo, the wing, and the eye. We will test the hypothesis that differentiation signals dominantly suppress the transcription of cell cycle control genes via an E2F/RB-independent mechanism. In Aim 1, we manipulate the activity of known cell cycle control genes to define the mechanism that triggers cell cycle exit, and we also analyze changes in gene expression during the exit process. In Aim 2, we study the transcriptional regulatory region of the critical cell cycle control gene, cyclin E, to identify cis-acting elements, and eventually trans-acting factors, that mediate its silencing at differentiation. In Aim 3 we perform genetic screens in the fly to identify novel genes that are functionally important for cell cycle exit. The combined results should distinguish between the many plausible explanations of cell cycle exit suggested in the literature, identify new gene products that mediate cell cycle exit, and provide a working paradigm for future studies of how differentiation signals interface with the cell cycle control apparatus. Because the genetic networks that orchestrate tissue patterning, cell differentiation, and cell cycle control are conserved between Drosophila and man, the results obtained herein should inform ongoing studies of human development and disease.
Funding Period: 2006-05-01 - 2010-04-30
more information: NIH RePORT

Top Publications

  1. pmc Combinatorial control of temporal gene expression in the Drosophila wing by enhancers and core promoters
    David D O'Keefe
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    BMC Genomics 13:498. 2012
  2. pmc The molecular chaperone Hsp90 is required for cell cycle exit in Drosophila melanogaster
    Jennifer L Bandura
    Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America German Cancer Research Center DKFZ Center for Molecular Biology Heidelberg ZMBH Alliance, Heidelberg, Germany
    PLoS Genet 9:e1003835. 2013
  3. pmc Temporal regulation of Dpp signaling output in the Drosophila wing
    David D O'Keefe
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
    Dev Dyn 243:818-32. 2014
  4. pmc A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo
    Laura A Buttitta
    Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    J Cell Biol 189:981-96. 2010
  5. ncbi A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila
    Laura A Buttitta
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Dev Cell 12:631-43. 2007
  6. pmc Mechanisms controlling cell cycle exit upon terminal differentiation
    Laura A Buttitta
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Curr Opin Cell Biol 19:697-704. 2007

Scientific Experts

  • Laura A Buttitta
  • David D O'Keefe
  • Bruce A Edgar
  • Jennifer L Bandura
  • Sean Thomas
  • Derek W Nickerson
  • Huaqi Jiang
  • Sean R Thomas
  • Kelsey Bolin
  • Ellen Griggs

Detail Information

Publications6

  1. pmc Combinatorial control of temporal gene expression in the Drosophila wing by enhancers and core promoters
    David D O'Keefe
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    BMC Genomics 13:498. 2012
    ..To identify genetic mechanisms that control epithelial differentiation, we analyzed the temporal patterns of gene expression during metamorphosis of the Drosophila wing...
  2. pmc The molecular chaperone Hsp90 is required for cell cycle exit in Drosophila melanogaster
    Jennifer L Bandura
    Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America German Cancer Research Center DKFZ Center for Molecular Biology Heidelberg ZMBH Alliance, Heidelberg, Germany
    PLoS Genet 9:e1003835. 2013
    ..Our results reveal that Hsp83 plays a heretofore unappreciated role in promoting APC/C function during cell cycle exit and suggest a mechanism by which Hsp90 inhibition could promote genomic instability and carcinogenesis. ..
  3. pmc Temporal regulation of Dpp signaling output in the Drosophila wing
    David D O'Keefe
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
    Dev Dyn 243:818-32. 2014
    ..It is likely that the Dpp signaling pathway regulates different sets of target genes at these two developmental time points...
  4. pmc A robust cell cycle control mechanism limits E2F-induced proliferation of terminally differentiated cells in vivo
    Laura A Buttitta
    Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    J Cell Biol 189:981-96. 2010
    ..These mechanisms are essential for proper development, as evading them leads to tissue outgrowths composed of dividing but terminally differentiated cells...
  5. ncbi A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila
    Laura A Buttitta
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Dev Cell 12:631-43. 2007
    ..In other cell types, however (e.g., wing epithelial cells), unknown mechanisms inhibit E2F and Cyclin/Cdk activity in parallel to enforce permanent cell cycle exit upon terminal differentiation...
  6. pmc Mechanisms controlling cell cycle exit upon terminal differentiation
    Laura A Buttitta
    Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
    Curr Opin Cell Biol 19:697-704. 2007
    ..This review focuses on describing recent advances in deciphering how terminal differentiation and exit from the cell cycle are coordinated...