title: Protein phosphatase 2A promotes the transition to G0 during terminal differentiation in Drosophila.
abstract: Protein phosphatase type 2A complex (PP2A) has been known as a tumor suppressor for over two decades, but it remains unclear exactly how it suppresses tumor growth. Here, we provide data indicating a novel role for PP2A in promoting the transition to quiescence upon terminal differentiation in vivo. Using Drosophila eyes and wings as a model, we find that compromising PP2A activity during the final cell cycle prior to a developmentally controlled cell cycle exit leads to extra cell divisions and delays entry into quiescence. By systematically testing the regulatory subunits of Drosophila PP2A, we find that the B56 family member widerborst (wdb) is required for the role of PP2A in promoting the transition to quiescence. Cells in differentiating tissues with compromised PP2A retain high Cdk2 activity when they should be quiescent, and genetic epistasis tests demonstrate that ectopic Cyclin E/Cdk2 activity is responsible for the extra cell cycles caused by PP2A inhibition. The loss of wdb/PP2A function cooperates with aberrantly high Cyclin E protein levels, allowing cells to bypass a robust G0 late in development. This provides an example of how loss of PP2A can cooperate with oncogenic mutations in cancer. We propose that the PP2A complex plays a novel role in differentiating tissues to promote developmentally controlled quiescence through the regulation of Cyclin E/Cdk2 activity.
authors.affiliation: University of Michigan, Department of Molecular, Cellular and Developmental Biology, Ann Arbor, MI 48109, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Sun
authors.affiliation: University of Michigan, Department of Molecular, Cellular and Developmental Biology, Ann Arbor, MI 48109, USA buttitta@umich.edu.
authors.forename: Laura
authors.initials: L
authors.lastname: Buttitta
mesh_terms: D000595:Amino Acid Sequence; D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000201:enzymology* / Q000235:genetics; D050684:E2F Transcription Factors / Q000378:metabolism; D004843:Epistasis, Genetic; D008969:Molecular Sequence Data; D038081:Organogenesis; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D021122:Protein Subunits / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D014157:Transcription Factors
chemical_list: D019927:Cyclin E; D029721:Drosophila Proteins; D050684:E2F Transcription Factors; C496298:E2f1 protein, Drosophila; D021122:Protein Subunits; D014157:Transcription Factors; D064173:Anaphase-Promoting Complex-Cyclosome; D051357:Cyclin-Dependent Kinase 2; C495887:cdk2 protein, Drosophila; D010749:Phosphoprotein Phosphatases; C079898:tws protein, Drosophila
keywords: Cell cycle; Quiescence; Terminal differentiation