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PIP degron-stabilized Dacapo/p21(Cip)(1) and mutations in ago act in an anti- versus pro-proliferative manner, yet both trigger an increase in Cyclin E levels
Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Hematopoiesis and Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Queensland, Australia.ORCID iD: 0000-0001-5095-541X
2019 (English)In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 13, article id UNSP dev175927Article in journal (Refereed) Published
Abstract [en]

During cell cycle progression, the activity of the CycE-Cdk2 complex gates S-phase entry. CycE-Cdk2 is inhibited by CDK inhibitors (CKIs) of the Cip/Kip family, which include the human p21(Cip)(1) and Drosophila Dacapo (Dap) proteins. Both the CycE and Cip/Kip family proteins are under elaborate control via protein degradation, mediated by the Cullin-RING ligase (CRL) family of ubiquitin ligase complexes. The CRL complex SCFFoxw7/Ago targets phosphorylated CycE, whereas p21(Cip)(1) and Dap are targeted by the CRLCdf2 complex, binding to the PIP degron. The role of CRL-mediated degradation of CycE and Cip/Kip proteins during CNS development is not well understood. Here, we analyse the role of ago (Fbxw7)-mediated CycE degradation, and of Dap and p21(Cip)(1) degradation during Drosophila CNS development. We find that ago mutants display over-proliferation, accompanied by elevated CycE expression levels. By contrast, expression of PIP degron mutant Dap and p21(Cip)(1) transgenes inhibit proliferation. However, surprisingly, this is also accompanied by elevated CycE levels. Hence, ago mutation and PIP degron Cip/Kip transgenic expression trigger opposite effects on proliferation, but similar effects on CycE levels.

Place, publisher, year, edition, pages
COMPANY BIOLOGISTS LTD , 2019. Vol. 146, no 13, article id UNSP dev175927
Keywords [en]
CKI; PIP degron; CNS proliferation; Protein degradation
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:liu:diva-159153DOI: 10.1242/dev.175927ISI: 000475477400019PubMedID: 31289041OAI: oai:DiVA.org:liu-159153DiVA, id: diva2:1339652
Note

Funding Agencies|Swedish Vetenskapsradet [2017-04061]; Knut och Alice Wallenbergs Stiftelse [KAW2012.0101]; Cancerfonden [CAN2017/257]; Royal Swedish Academy of Sciences

Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2019-11-13

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