To ensure an even segregation of chromosomes during somatic cell division, eukaryotes rely on mitotic spindles. Here, we measured prime characteristics of the Arabidopsis mitotic spindle and built a three-dimensional dynamic model using Cytosim. We identified the cell-cycle regulator CYCLIN-DEPENDENT KINASE B1 (CDKB1) together with its cyclin partner CYCB3;1 as key regulators of spindle morphology in Arabidopsis. We found that the augmin component ENDOSPERM DEFECTIVE1 (EDE1) is a substrate of the CDKB1;1-CYCB3;1 complex. A non-phosphorylatable mutant rescue of ede1 resembled the spindle phenotypes of cycb3;1 and cdkb1 mutants and the protein associated less efficiently with spindle microtubules. Accordingly, reducing the level of augmin in simulations recapitulated the phenotypes observed in the mutants. Our findings emphasize the importance of cell-cycle-dependent phospho-control of the mitotic spindle in plant cells and support the validity of our model as a framework for the exploration of mechanisms controlling the organization of the eukaryotic spindle.

Cyclins and cyclin-dependent kinases (CDKs) localize to the centrosome, but their significance in the cell cycle is unclear. Recently, Roberts et al. revealed that centrosomal cyclin B-CDK is required for mitotic entry and phosphorylation of substrates. This suggests that the centrosome acts as a signaling hub controlling the cell cycle.

The cell cycle comprises sequential events during which a cell duplicates its genome and divides it into two daughter cells. This process is tightly regulated to ensure that the daughter cell receives identical copied chromosomal DNA and that any errors in the DNA during replication are correctly repaired. Cyclins and their enzyme partners, cyclin-dependent kinases (CDKs), are critical regulators of G- to M-phase transitions during the cell cycle. Mitogenic signals induce the formation of the cyclin/CDK complexes, resulting in phosphorylation and activation of the CDKs. Once activated, cyclin/CDK complexes phosphorylate specific substrates that drive the cell cycle forward. The sequential activation and inactivation of cyclin-CDK complexes are tightly controlled by activating and inactivating phosphorylation events induced by cell-cycle proteins. The non-coding RNAs (ncRNAs), which do not code for proteins, regulate cell-cycle proteins at the transcriptional and translational levels, thereby controlling their expression at different cell-cycle phases. Deregulation of ncRNAs can cause abnormal expression patterns of cell-cycle-regulating proteins, resulting in abnormalities in cell-cycle regulation and cancer development. This review explores how ncRNA dysregulation can disrupt cell division balance and discusses potential therapeutic approaches targeting these ncRNAs to control cell-cycle events in cancer treatment.

Meiosis is a complex variant of the mitotic cell cycle, and as such relies on many of the same proteins involved in mitosis, but utilizes these in novel ways. As in mitosis, Cdk1 and its cyclin partners, Cyclin A, B, and B3 are required at multiple steps in meiosis. Here, we study the effect of stabilized forms of the three mitotic cyclins to study the consequences of failure to degrade the cyclins in meiosis. We find that stabilized Cyclin B3 promotes ectopic microtubule polymerization throughout the egg, dependent on APC/C activity and apparently due to the consequent destruction of Cyclin A and Cyclin B. We present data that suggests CycB, and possibly CycA, can also promote APC/C activity at specific stages of meiosis. We also present evidence that in meiosis APC/CCort and APC/CFzy are able to target Cyclin B via a novel degron. Overall, our findings highlight the distinct functions of the three mitotic Cdk-cyclin complexes in meiosis.

Skp2, the substrate recognition component of the SCFSkp2 ubiquitin ligase, has been implicated in the targeted destruction of a number of key cell cycle regulators and the promotion of S-phase. One of its critical targets is the Cyclin dependent kinase (Cdk) inhibitor p27, and indeed the overexpression of Skp2 in a number of cancers is directly correlated with the premature degradation of p27. Skp2 was first identified as a protein that interacts with Cyclin A in transformed cells, but its role in this complex has remained unclear. In this paper, we demonstrate that Skp2 interacts with Cyclin A in Drosophila and is required to maintain Cyclin A levels and permit mitotic entry. Failure of mitotic entry in Skp2 mutant cells results in polyploidy. If these cells enter mitosis again they are unable to properly segregate their chromosomes, leading to checkpoint dependent cell cycle arrest or apoptosis. Thus, Skp2 is required for mitosis and for maintaining diploidy and genome stability.

Sall1 and Sall4 (Sall1/4), zinc-finger transcription factors, are expressed in the progenitors of the second heart field (SHF) and in cardiomyocytes during the early stages of mouse development. To understand the function of Sall1/4 in heart development, we generated heart-specific Sall1/4 functionally inhibited mice by forced expression of the truncated form of Sall4 (ΔSall4) in the heart. The ΔSall4-overexpression mice exhibited a hypoplastic right ventricle and outflow tract, both of which were derived from the SHF, and a thinner ventricular wall. We found that the numbers of proliferative SHF progenitors and cardiomyocytes were reduced in ΔSall4-overexpression mice. RNA-sequencing data showed that Sall1/4 act upstream of the cyclin-dependent kinase (CDK) and cyclin genes, and of key transcription factor genes for the development of compact cardiomyocytes, including myocardin (Myocd) and serum response factor (Srf). In addition, ChIP-sequencing and co-immunoprecipitation analyses revealed that Sall4 and Myocd form a transcriptional complex with SRF, and directly bind to the upstream regulatory regions of the CDK and cyclin genes (Cdk1 and Ccnb1). These results suggest that Sall1/4 are critical for the proliferation of cardiac cells via regulation of CDK and cyclin genes that interact with Myocd and SRF.

Androgen-independent prostate cancer accounts for mortality in the world. In this study, various extracts of a medical fungus dubbed Ganoderma formosanum were screened for inhibition of DU145 cells, an androgen-independent prostate cancer cell line. Results demonstrated that both hexane (GF-EH) and butanol (GF-EB) fraction of G. formosanum ethanol extract inhibited DU145 cell viability in a dose-dependent manner. GF-EH induced cell-cycle arrest in G1 phase of DU145 cells via downregulation of cyclin E2 protein expression. In addition, GF-EB triggered extrinsic apoptosis of DU145 cells by activating caspase 3 gene expression resulting in programed cell death. Above all, both GF-EH and GF-EB show lower toxicity to normal human fibroblast cell line compared to DU145 cell, implying that they possess specific drug action on cancer cells. This study provides a molecular basis of G. formosanum extract as a potential ingredient for treatment of androgen-independent prostate cancer.

OBJECTIVE: Aspergillus fumigatus has been included by the World Health Organization in the priority list of fungal pathogens because (i) it causes 90% of invasive aspergillosis cases, with a high mortality rate, and (ii) infections are becoming increasingly resistant to azole antifungals. A. nidulans is an opportunistic pathogen and a saprotroph which has served during the last 80 years as a reference system for filamentous fungi. Here, we characterized the role in morphogenesis and development of the putative transcriptional cyclin/kinase complex CTDK-1 in both aspergilli. The null mutants of the corresponding genes showed delayed germination, aberrant conidiophore development, and inhibition of cleistothecia production. While in higher eukaryotes this complex is formed only by a cyclin and a kinase, the fungal complex would incorporate a fungal-specific third component, FlpB, which would enable the interaction between the kinase (Stk47) and the cyclin (FlpA) and may be used as a target for antifungals.

The cell cycle is a complex process that involves DNA replication, protein expression, and cell division. Dysregulation of the cell cycle is associated with various diseases. Cyclin-dependent kinases (CDKs) and their corresponding cyclins are major proteins that regulate the cell cycle. In contrast to inhibition, a new approach called proteolysis-targeting chimeras (PROTACs) and molecular glues can eliminate both enzymatic and scaffold functions of CDKs and cyclins, achieving targeted degradation. The field of PROTACs and molecular glues has developed rapidly in recent years. In this article, we aim to summarize the latest developments of CDKs and cyclin protein degraders. The selectivity, application, validation and the current state of each CDK degrader will be overviewed. Additionally, possible methods are discussed for the development of degraders for CDK members that still lack them. Overall, this article provides a comprehensive summary of the latest advancements in CDK and cyclin protein degraders, which will be helpful for researchers working on this topic.

The cell cycle is the series of events that occur in a cell leading to its division and duplication. It can be divided into two main stages: interphase and mitosis. Interphase is the longest stage of the cell cycle and can be further divided into three phases: G1, S, and G2. During G1, the cell grows and prepares for DNA synthesis. In the S phase, DNA synthesis occurs, leading to the replication of the genetic material. In G2, the cell continues to grow and prepares for mitosis. After mitosis, the cell enters the final stage of the cell cycle, called cytokinesis, during which the cytoplasm is divided, resulting in two separate daughter cells. The cell cycle then begins again with interphase. Cell cycle dysregulation is a hallmark of cancer, and it can have several consequences that contribute to the development and progression of cancer. Cyclin inhibitors and checkpoint activators have shown promise in the treatment of cancer, particularly in combination with other therapies.