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Permanent link (DOI): https://doi.org/10.7939/R3000077C

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Analysis of Developmental Relevance of Cdk1 Inhibitory Phosphorylation in Drosophila Open Access

Descriptions

Other title
Subject/Keyword
Wing disc
Spermatocytes
Inhibitory Phosphorylation
Cdk1
Drosophila
Checkpoint
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Ayeni, Joseph O
Supervisor and department
Dr S.D. Campbell (Biological Sciences)
Examining committee member and department
Dr. Lisa Stein (Biological Sciences)
Dr. Marty Srayko (Biological Sciences)
Dr Esther Verheyen (External Examiner)
Dr. S.D. Campbell (Biological Sciences)
Dr. John Locke (Biological Sciences)
Dr. Frank Nargang (Biological Sciences)
Department
Department of Biological Sciences
Specialization
Molecular Biology and Genetics
Date accepted
2014-01-09T08:52:34Z
Graduation date
2014-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Cyclin dependent kinase 1, Cdk1, inhibitory phosphorylation is at the core of conserved checkpoint mechanisms that prevent mitosis from interfering with DNA replication or repair. It is also crucial for coordinating cell cycle progression with morphogenetic processes during organismal development. During interphase, Wee1 and Myt1 function as Cdk1 inhibitory kinases. Both kinases phosphorylate Cdk1 on a conserved tyrosine, Y15, however the dual specificity Myt1 kinase also phosphorylates an adjacent threonine, T14. In spite of the functional redundancy with Wee1 for Y15 phosphorylation, Myt1 serves specialized developmental functions that may reflect its unique capabilities as a T14 or dual specificity Cdk1 inhibitor. To define distinct developmental requirements for T14 and Y15 as well as dual phosphorylation of Cdk1, new transgenic strains expressing Gal4-inducible VFP-tagged wild-type Cdk1 and three Cdk1 phospho-acceptor mutants: Cdk1(T14A)-VFP, Cdk1(Y15F)-VFP and Cdk1(T14AY15F)-VFP, were engineered. Genetic and biochemical evidence revealed that T14 and Y15 inhibitory phosphorylation are functionally distinct mechanisms for regulating Cdk1 activity. Y15 inhibitory phosphorylation was shown to be necessary and sufficient for developmentally regulated G2 phase arrest, while the T14 phosphorylation of Cdk1 may have evolved as a mechanism for accumulating dually inhibited Cdk1-Cyclin B complexes. The Myt1-mediated dual phosphorylation of Cdk1 was implicated as a genetic innovation evolved in metazoans for allowing cells to remain stably arrested in G2 phase for prolonged periods. The new transgenic tools were also used to define how the temporal regulation of Cdk1 and the timing of G2-phase quiescence are linked with the developmentally regulated signal crucial for specifying neuronal cell fate during sensory organ development in Drosophila. Genetic evidence demonstrated that forced mitosis in G2 quiescent SOP cells conferred self-renewal potential on the cells that would normally terminally differentiate. Thus, linking the timing of G2 quiescence in SOP cells to the critically important developmental choice of self-renewal versus terminal differentiation. Further analysis of the transgenic Cdk1 fusion proteins in cdc25twe mutant spermatocytes, lacking active endogenous Cdk1 proteins, suggested the existence of both Cdc25Twe-dependent and –independent regulation of Cdk1 activity in male meiosis.
Language
English
DOI
doi:10.7939/R3000077C
Rights
This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for the purpose of private, scholarly or scientific research. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
Citation for previous publication
Ayeni J.O et al, 2014. Dual phosphorylation of cdk1 coordinates cell proliferation with key developmental processes in Drosophila, Genetics v196 (1).

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