Per citar aquest document: http://ddd.uab.cat/record/117061
Testing the cell cycle phase specificity of cyclins : can an earlier cyclin trigger a later event? / Asrar Ahmad Malik ; [thesis director: David Garcia Quintana]
Asrar Ahmad, Malik
Garcia i Quintana, David, dir. (Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular)
Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular

Publicació: [Barcelona] : Universitat Autònoma de Barcelona, 2013
Descripció: 1 recurs electrònic (165 p.)
Resum: Progression through the cell cycle is directed by cyclin dependent kinases (CDKs), which are essential for normal and cancer cell proliferation. CDKs are activated by association with cyclins specific to each cell cycle phase (G1, S, G2, and M). Thus, CDK associated with G1 phase cyclins promote the expression of proteins necessary for DNA replication, but is unable to activate it. CDK associated with S phase cyclins, in turn, triggers the activation of chromosomal origins of replication, but is unable to promote chromosome condensation and segregation of sister chromatids, which is carried out by CDK associated with mitotic cyclins. Despite the essential role of CDKs in cell cycle progression, how the different cyclins promote specifically the various processes of the cell cycle was still an open question by the time this thesis was initiated. Since the discovery of cyclins by Nobel laureate Tim Hunt [Evans et al. (1983) Cell 33:389] it was assumed that cyclins confer substrate specificity. However, later on, fellow Nobel laureate Paul Nurse proposed an alternative quantitative model, [Stern & Nurse (1996) Trends Genet 12:345], based on the observation that successive waves of cyclins result in increased levels of CDK activity. While low levels of activity (CDK associated with G1 cyclins) are sufficient promote progression through the G1 phase and start the pro-S phase transcription program, would be unable to trigger replication. Moderate levels of activity (CDK associated with S phase cyclins) would be able to activate replication but not mitosic events, which would require the high CDK activity associated with M phase cyclins. If correct, the quantitative model should fulfill two predictions, but only one was demonstrated by the Nurse lab. Eukaryotic unicellular yeast cells are able to survive with a single mitotic cyclin, which is notwithstanding able to orderly drive the cell through the different cell cycle phases [Fisher & Nurse (1996) EMBO J 15:850]. Therefore M-CDK activity is able to promote the previous phases of the cycle in the fission yeast Schizosaccharomyces pombe However, if a purely quantitative mechanism applies, the complementary prediction should be true as well: an early cyclin to be able to trigger later events if expressed at levels high enough. To test such prediction we generated a budding yeast Saccharomyces cerevisiae strain carrying a G1 cyclin G1 resistant to degradation, under a strong inducible promoter, and fused to a nuclear localization signal. Our results show that one such cyclin is capable of firing chromosome replication conditions in which the S phase cyclins, G2 and M are suppressed. Therefore, our results support the quantitative model against the requirement of substrate specificity. How eukaryotic cells prevent premature activation of the critical cell cycle processes that lead to genomic instability, seems therefore trust in the regulation of activity levels and limiting the presence of cyclin at specific time and space.
Nota: Tesi doctoral - Universitat Autònoma de Barcelona. Departament de Bioquímica i Biologia Molecular, 2013
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Llengua: Anglès
Document: Tesis i dissertacions electròniques ; doctoralThesis
Matèria: Cicle de la cèl·lula ; Ciclines ; Quinases dependents de ciclina
ISBN: 9788449039300

Adreça alternativa: http://hdl.handle.net/10803/127221


165 p, 7.6 MB

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