Cell cycle checkpoint regulators reach a zillion

Yasutis, Kimberly; Kozminski, Keith G.

doi:10.4161/cc.24637

Cited by 53 publications

(47 citation statements)

References 133 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cell cycle checkpoints halt the cycle or even cause the exit from the cycle. These stops are used for control of integrity and repair of the genetic material (Yasutis and Kozminski 2013;Shaltiel et al 2015;Wang et al 2015). Therefore, the relaxation of these checkpoints should accelerate the cycle.…”

Section: Discussionmentioning

confidence: 99%

Accelerated pathway evolution in mouse-like rodents involves cell cycle control

Vinogradov

2015

Mamm Genome

View full text Add to dashboard Cite

Rodents include both the cancer-susceptible short-lived mouse and the two unrelated cancer-resistant long-lived mole-rats. In this work, their genomes were analyzed with the goal to reveal pathways enriched in genes, which are more similar between the mole-rats than between the mouse and the naked mole-rat. The pathways related to cell cycle control were prominent. They include external signal transduction and all cell cycle stages. There are several stem cell pathways among them. The other enriched pathways involve ubiquitin-dependent protein degradation, immunity, mRNA splicing, and apoptosis. The ubiquitin-dependent protein degradation is a core of network of enriched pathways. However, this phenomenon is not specific for the mouse and the mole-rats. The other muroid species show features similar to the mouse, whereas the non-muroid rodents and the human show features similar to the mole-rats. The higher ratio of non-synonymous to synonymous nucleotide substitutions (dN/dS) indicates the accelerated evolution of revealed pathways in the muroid rodents (except the blind mole-rat). Paradoxically, the dN/dS averaged over the whole genome is lower in the muroids, i.e., the purifying selection is generally stronger in them. In practical sense, these data suggest caveat for using muroid rodents (mouse, rat, and hamsters) as biomedical models of human conditions involving cell cycle and show the network of pathways where muroid genes are most different (compared with non-muroid) from human genes. The guinea pig is emphasized as a more suitable rodent model for biomedical research involving cell cycle.

show abstract

Section: Discussionmentioning

confidence: 99%

Accelerated pathway evolution in mouse-like rodents involves cell cycle control

Vinogradov

2015

Mamm Genome

View full text Add to dashboard Cite

show abstract

“…Of note, Nrf2 null mice are highly susceptible to chemical-induced carcinogenesis (16,19,30,34). The misregulation of mitotic entry is often oncogenic (35). Therefore, it is possible that the regenerative response to chemical-induced tissue injury in cells deficient in Nrf2 prevents timely M phase entry, which promotes tumor formation.…”

Section: Discussionmentioning

confidence: 99%

Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration

Zou

Lee

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates various cellular activities, including redox balance, detoxification, metabolism, autophagy, proliferation, and apoptosis. Several studies have demonstrated that Nrf2 regulates hepatocyte proliferation during liver regeneration. The aim of this study was to investigate how Nrf2 modulates the cell cycle of replicating hepatocytes in regenerating livers. Wildtype and Nrf2 null mice were subjected to 2/3 partial hepatectomy (PH) and killed at multiple time points for various analyses. Nrf2 null mice exhibited delayed liver regrowth, although the lost liver mass was eventually restored 7 days after PH. Nrf2 deficiency did not affect the number of hepatocytes entering the cell cycle but did delay hepatocyte mitosis. Mechanistically, the lack of Nrf2 resulted in increased mRNA and protein levels of hepatic cyclin A2 when the remaining hepatocytes were replicating in response to PH. Moreover, Nrf2 deficiency in regenerating livers caused dysregulation of Wee1, Cdc2, and cyclin B1 mRNA and protein expression, leading to decreased Cdc2 activity. Thus, Nrf2 is required for timely M phase entry of replicating hepatocytes by ensuring proper regulation of cyclin A2 and the Wee1/Cdc2/cyclin B1 pathway during liver regeneration. nuclear factor erythroid 2-related factor 2; hepatocyte mitosis; hepatocyte proliferation NUCLEAR FACTOR ERYTHROID 2-related factor 2 (Nrf2) is a basic leucine zipper region-containing transcription factor that is abundantly expressed in many tissues such as the liver (6). The activity of Nrf2 is regulated by multiple mechanisms, including gene transcription, kelch-like ECH-associated protein 1-mediated proteasome degradation, and kinase-mediated phosphorylation. The sequential events leading to Nrf2 activation include nuclear translocation, heterodimer formation with small Maf portions, binding to an antioxidant response element (ARE), and transactivation of Nrf2 target genes. There are both direct and indirect Nrf2 target genes involved in various cellular functions, including detoxification, metabolism, autophagy, proliferation, differentiation, and apoptosis (3,13,17,26). Previous studies have demonstrated that Nrf2 regulates the hepatocyte proliferative response to liver mass loss (2,33). The aim of the present study was to investigate how Nrf2 modulates the cell cycle progression of replicating hepatocytes during liver repair.Partial hepatectomy (PH) induces highly synchronized entry and progression of the cell cycle in residual hepatocytes. Thus, PH is widely used as an in vivo model to study the regulation of cell proliferation (23). We performed PH on wild-type and Nrf2 null mice and compared the cell cycle progression of replicating hepatocytes. Our data indicate that Nrf2 is a regulator of hepatocyte mitosis.

show abstract

“…Checkpoint mechanisms slow down or arrest the cell cycle to enable cells to fix damage or to obtain the required metabolites before proceeding and are as such important for the integrity of cell division (20)(21)(22). According to this critical function in quality control, mutations in checkpoint genes in mammals have been linked to cancer predisposition and progression.…”

mentioning

confidence: 99%

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Chauhan

Visram

Cristobal-Sarramian

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cell growth and division requires the precise duplication of cellular DNA content but also of membranes and organelles. Knowledge about the cell-cycle-dependent regulation of membrane and storage lipid homeostasis is only rudimentary. Previous work from our laboratory has shown that the breakdown of triacylglycerols (TGs) is regulated in a cell-cycle-dependent manner, by activation of the Tgl4 lipase by the major cyclin-dependent kinase Cdc28. The lipases Tgl3 and Tgl4 are required for efficient cell-cycle progression during the G1/S (Gap1/replication phase) transition, at the onset of bud formation, and their absence leads to a cell-cycle delay. We now show that defective lipolysis activates the Swe1 morphogenesis checkpoint kinase that halts cell-cycle progression by phosphorylation of Cdc28 at tyrosine residue 19. Saturated longchain fatty acids and phytosphingosine supplementation rescue the cell-cycle delay in the Tgl3/Tgl4 lipase-deficient strain, suggesting that Swe1 activity responds to imbalanced sphingolipid metabolism, in the absence of TG degradation. We propose a model by which TG-derived sphingolipids are required to activate the protein phosphatase 2A (PP2A Cdc55 ) to attenuate Swe1 phosphorylation and its inhibitory effect on Cdc28 at the G1/S transition of the cell cycle.T he eukaryotic cell cycle is a highly coordinated and conserved process. In addition to DNA replication, one of the major requirements for the cell to progress through the cell cycle is the precise duplication of membrane-enclosed organelles and other cellular components before cell division. Knowledge about the mechanisms regulating (membrane) lipid homeostasis during the cell cycle is scarce (1), however several levels of evidence suggest regulation of key enzymes of lipid metabolism in a cell-cycledependent manner. The PAH1-encoded phosphatidic acid (PA) phosphatase (Pah1), a key enzyme of triacylglycerol (TG) synthesis that provides the TG precursor diacylglycerol (DG), is phosphorylated and inactivated by the cyclin-dependent kinases Cdc28 and Pho85-Pho80 (2, 3). Kurat et al. showed that Tgl4, next to Tgl3, one of the two major TG lipases in yeast and the ortholog of mammalian ATGL (4, 5), is also phosphorylated by Cdc28. In contrast to Pah1, however, Tgl4 is activated by Cdc28 (6). This inverse regulation of Pah1 and Tgl4 by Cdc28-dependent phosphorylation led to the model by which the TG content oscillates during the cell cycle: On the one hand, TG synthesis serves as a buffer for excess de novo generated fatty acids (FAs), and on the other hand, in times of increased demand-that is, at the onset of bud formation and bud growth-Tgl4-catalyzed lipolysis becomes active to provide TG-derived precursors for membrane lipid synthesis (6).TG and membrane phospholipids share the same intermediates, PA and DG; PA is generated by sequential acylation of glycerol-3-phosphate, reactions that mostly take place in the endoplasmic reticulum (ER) membrane (7). The dephosphorylation of PA to DG by the PAH1-encoded PA phosphatase Pah1 is ...

show abstract

Cell cycle checkpoint regulators reach a zillion

Cited by 53 publications

References 133 publications

Accelerated pathway evolution in mouse-like rodents involves cell cycle control

Accelerated pathway evolution in mouse-like rodents involves cell cycle control

Nrf2 is essential for timely M phase entry of replicating hepatocytes during liver regeneration

Morphogenesis checkpoint kinase Swe1 is the executor of lipolysis-dependent cell-cycle progression

Contact Info

Product

Resources

About