Tour-de-Force

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Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007important role in bringing the oxidized GSSG back into its reduced form the GSH (Boonstra and Post,2004).Table 1.2: Most important antioxidantsSource: Schrader and Fahimi, 2004Influences of ROS on the cell cycleInterest in ROS as a possible regulator of the cell cycle has increased in the last decade, as the initial viewof ROS being merely an undesired side product of metabolic processes of the cell has lost its credibility(Menon and Goswami, 2007). Several studies have shown that ROS, besides from being toxic to the cellin high concentrations, can be useful in regulation of processes such as apoptosis and proliferation (Rheeet al., 1999). These two opposing effects of ROS might seem contradictory but can easily be explained bydifferent ROS types, levels, localization and exposure time. Indeed, several recent reviews suggest athreshold concept indicating that different ROS levels can have distinct effects on the cell (Menon andGoswami, 2007). Depending on its concentration and exposure time, ROS can have effects ranging fromenhanced proliferation to apoptosis (Boonstra and Post, 2004).It has been suggested that ROS can function as a secondary messenger in signal transductionand play a role in production of signaling molecules (Bae et al., 2000). Moreover, some reports suggestthat ROS can alter a protein, for instance PKC, by directly interacting with its cysteine residues whichcould result in change in activity (Klann et al., 2000).Cell cycle progression pathways influenced by ROSSince ROS can have diverse effects on the cell cycle, it is not surprising that many different processesinvolved in cell cycle regulation have been found to be influenced by ROS (Finkel et al., 2000). Productionof ligand-stimulated ROS activates proteins like mitogen-activated protein kinase (MAPK) (Brar et al.,1999), protein kinase C (PKC) (Junn et al., 2000) and epidermal growth factor (EGF) (Bae et al., 1997),which are all important proteins in control of cell proliferation. Conour and colleagues (2004) usedbioinformatics to identify 92 proteins involved in cell cycle regulation that can possibly be regulated byROS. Ten percent of these proteins function in S phase and twenty percent function in G1 phase, whereashalf of the identified proteins function in G2 and M.Transition from one phase of cell cycle to next is tightly controlled so that cell cycle progression proceedsonly when the cell is ready to continue (Boonstra and Post, 2004). These transitions and successfulprogression through the cell cycle are largely controlled by the activity of cdk-cyclin complexes (Morgan etal., 1997; Nigg et al., 2001). Regulation of cell cycle progression is largely dependent on ubiquitination ofproteins of cdk-cyclin complex (Reed et al., 2003). ROS is reported to influence the ubiquitin pathway.Introduction of hydrogen peroxide decreased the activities of ubiquitin-activating and -conjugatingenzymes (Jahngen-Hodge et al., 1997). It is possible that ROS play a role in regulation of the activity ofthe cdk-complexes by altering ubiquitin pathways.G1/S transition dependency on ROS levelsA recent study by Havens and colleagues (2006) suggested that ROS are required for progression fromG1 to S phase. When ROS levels were decreased by treatment of cells with antioxidants, cells can stillgrow but cell cycle progression is halted. The arrest is shown to be due to decreased cyclin A presence.Cyclin A accumulation in late G1 is essential for the activation of cdk2-cyclin A complex which is essentialfor progression into S phase, because the complex initiates DNA synthesis.Mitotic kinases and progression into M phaseSCI 332 Advanced Molecular Cell Biology Research Proposal 14
Tour-de-Force: Interplay between Mitochondria and Cell Cycle Progression Fall 2007In the G2/M phase, cyclin A, cyclin B and cyclin D are present. Several studies have shown that cdk1activity is indispensable for transition from G 2 into mitosis. Other mitotic kinase families such as the Pololikekinase family, and the NIMA family have been shown to be active in the transition but their contributionto entry into mitosis is not as well-understood as the contribution of cdk1. Cdk1 knock-out cells couldneither divide nor survive (Harborth et al., 2001). This finding suggests that even if other ckds areupregulated in absence of cdk1, it is not sufficient for progression into M phase.Cdk1 can bind to cyclin types A and B and cells lacking cyclin A or cyclin B cannot enter mitosis.Sanchez et al. (2005) suggest that the cdk2-cyclin A complex is also present in G 2 /M transition; itspresence, however, is not required for cell cycle progression. Cyclin D is also present but cyclin D’sbinding partners cdk4 and cdk6 are not required for transition from G2 to M (Nigg et al., 2001; Morgan etal., 1997). In short, cdk1-cyclin A/B complexes are most obviously essential for the G2/M transition.Cyclin A&B levels are regulated by APC activityIn the study by Havens et al. (2006) decreased cyclin A levels were shown to be due to altered activity ofanaphase-promoting complex (APC) which targets cyclin A for degradation. The exact reason behind thechanged activity of APC has not been identified, but a change in activity of the APC-inhibitor Emi1 isexpected to be the reason (Havens et al., 2006). ROS might either have a direct effect on APC, or canaffect its activity through effects on Emi1.APC is a protein-ubiquitin ligase that conjugates ubiquitin to its substrates targeting it fordegradation by the 26S proteosome. APC plays an essential role in the spindle checkpoint in mitosis.Cyclins A and B are needed for entry into mitosis, but need to be degraded for mitosis to proceed. Levelsof cyclin A and cyclin B, but not of Cyclin D, are regulated by their transcription and by inhibition andactivation of APC. APC has to be bound to its co-factors Cdh1 or Cdc20 to be active. APC is activated inmetaphase and is active in the rest of mitosis. During metaphase and anaphase, APC is bound to Cdc20,to target cyclin A and cyclin B for degradation and thus stimulate exit from mitosis.At the end of anaphase APC is still active but bound to Cdh1. APC stays bound to Cdh1 until lateG1, when it is inhibited by Emi1 activity which phosphorylates Cdh1 causing its dissociation from APC.Emi1 can also phosphorylate Cdc20 preventing its association with APC. Cdc20 is only transcribed at thestart of mitosis and is degraded after anaphase; its regulation is therefore mainly on the level oftranscription. Cdh1 is present throughout the cell cycle and has to be inhibited in late G1 and also in G2/M.In the G 1 /S transition Cdh1 has to be inhibited by phosphorylation so that essential cyclin A canaccumulate. Similar to the G 1 /S transition, Cdh1 has to be phosphorylated by Emi1 in G 2 /M so that cyclinA and cyclin B can accumulate, which is necessary for entry into mitosis (Reed et al., 2003; Zhou et al.,2002; Sudo et al., 2001; Hames et al., 2001). A similar regulation in G 2 /M as in G 1 /S suggests that theG 2 /M transition can also be dependent on ROS levels.SCI 332 Advanced Molecular Cell Biology Research Proposal 15
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