Cell cycle control: many ways to skin a cat

Thirty exponential cell divisions after fertilization would produce the number of cells in a baby mouse, but would not make a mouse. Sophisticated controls govern the cell cycle during development. These controls appear to play a central role in sculpting biological form. Rapid advances in our understanding of the machinery that drives the cell cycle provide a foundation for investigation of the molecular nature of cell cycle control in development. In this article, I emphasize that the design of the cell cycle machinery provides numerous inputs for regulation. I hope that the emphasis I have chosen will avert a tendency towards a narrow perception of cell cycle control.     

Wagging the dogma; tissue-specific cell cycle control in the mouse embryo

The family of cyclin-dependent kinases (Cdks) lies at the core of the machinery that drives the cell division cycle. Studies in cultured mammalian cells have provided insight into the cellular functions of many Cdks. Recent Cdk and cyclin knockouts in the mouse show that the functions of G1 cell cycle regulatory genes are often essential only in specific cell types, pointing to our limited understanding of tissue-specific expression, redundancy, and compensating mechanisms in the Cdk network.     

Two-way communication between the metabolic and cell cycle machineries: the molecular basis

The relationship between cellular metabolism and the cell cycle machinery is by no means unidirectional. The ability of a cell to enter the cell cycle critically depends on the availability of metabolites. Conversely, the cell cycle machinery commits to regulating metabolic networks in order to support cell survival and proliferation. In this review, we will give an account of how the cell cycle machinery and metabolism are interconnected. Acquiring information on how communication takes place among metabolic signaling networks and the cell cycle controllers is crucial to increase our understanding of the deregulation thereof in disease, including cancer.     

Reverse the curse--the role of deubiquitination in cell cycle control

Reversible protein ubiquitination is a crucial mechanism regulating the progression through the eukaryotic cell cycle. Ubiquitin-dependent signaling is terminated by specific deubiquitinating enzymes (DUBs), which now are known to be integral components of the core cell cycle machinery and cell cycle checkpoints. The importance of DUBs for cell cycle control is underscored by their frequent misregulation in cancer. Here, we discuss the role of deubiquitinating enzymes in controlling proliferation.     

Aspergillus nidulans as a model system to characterize the DNA damage response in eukaryotes

Interest in DNA repair in Aspergillus nidulans had mainly grown out of studies of three different biological processes, namely mitotic recombination, inducible responses to detrimental environmental changes, and genetic control of the cell cycle. Ron Morris started the investigation of the genetic control of the cell cycle by screening hundreds of cell cycle temperature sensitive Aspergillus mutants. The sequencing and innovative analysis of these genes revealed not only several components of the cell cycle machinery that are directly involved in checkpoint response, but also components required for DNA replication and DNA damage response machinery. Here, we will provide an overview about currently known aspects of the DNA damage response in A. nidulans. Emphasis is put on analyzed mutants that are available and review epistatic relationships and other interactions among them. Furthermore, a comprehensive list of A. nidulans genes involved in different processes of the DNA damage response, as identified by homology of genome sequences with well-characterized human and yeast DNA repair genes, is shown.     

Quantitative proteomics reveals the basis for the biochemical specificity of the cell-cycle machinery

Cyclin-dependent kinases comprise the conserved machinery that drives progress through the cell cycle, but how they do this in mammalian cells is still unclear. To identify the mechanisms by which cyclin-cdks control the cell cycle, we performed a time-resolved analysis of the in vivo interactors of cyclins E1, A2, and B1 by quantitative mass spectrometry. This global analysis of context-dependent protein interactions reveals the temporal dynamics of cyclin function in which networks of cyclin-cdk interactions vary according to the type of cyclin and cell-cycle stage. Our results explain the temporal specificity of the cell-cycle machinery, thereby providing a biochemical mechanism for the genetic requirement for multiple cyclins in vivo and reveal how the actions of specific cyclins are coordinated to control the cell cycle. Furthermore, we identify key substrates (Wee1 and c15orf42/Sld3) that reveal how cyclin A is able to promote both DNA replication and mitosis.     

Green light for the cell cycle

In recent years, considerable progress has been made in unraveling the control mechanisms operating on the plant cell cycle and most of the key regulators have now been identified, including cyclin-dependent kinases (CDKs), cyclins, CDK-inhibitory proteins, the WEE kinase and proteins of the retinoblastoma-related protein (RBR)/E2F/DP pathway. The review discusses recent developments in our understanding of the plant cell cycle machinery and highlights the role of the cell cycle in plant development.     

pRb and the cdks in apoptosis and the cell cycle

Apoptosis is a fundamental biological process present in metazoan cells. Linking apoptosis to the cell cycle machinery provides a mechanism to maintain proper control of cell proliferation in a multicellular organism. pRb and the cyclin-dependent kinases may have dual roles as integral components of the cell cycle and regulators of apoptosis. In many instances manipulation of the cell cycle through these molecules can induce or inhibit apoptosis. Recent studies also identify pRb as a substrate for an apoptotic protease; however, other cell cycle components are not known substrates. While it is clear that many common molecules can affect cell proliferation and cell death, the universality of any one cell cycle molecule in apoptosis has yet to be determined.     

Cell cycle and cell fate interactions in neural development

Mechanisms coupling cell cycle and cell fate operate at different steps during neural development. Intrinsic factors control the cell proliferation of distinct brain regions and changes of cell fate competence, whereas components of the cell cycle machinery could play a major role in setting the appropriate timing of the generation of different cell types.     

Function of cyclins in regulating the mitotic and meiotic cell cycles in male germ cells

The unique cell cycles that characterize various aspects of the differentiation of germ cells provide a unique opportunity to understand heretofore elusive aspects of the in vivo function of cell cycle regulators. Key components of the cell cycle machinery are the regulatory sub-units, the cyclins, and their catalytic partners, the cyclin-dependent kinases. Some of the cyclins exhibit unique patterns of expression of germ cells that suggest possible concomitant distinct functions, predictions that are being explored by targeted mutagenesis in mouse models. A novel, meiosis-specific function has been shown for one of the A-type cyclins, cyclin A1. Embryonic lethality has obviated understanding of the germline functions of cyclin A2 and cyclin B1, while yet other cyclins, although expressed at specific stages of germ cell development, may have less essential function in the male germline.     

Beyond proliferation--cell cycle control of neuronal survival and differentiation in the developing mammalian brain

Cell cycle proteins are critical regulators of proliferation in dividing cells. Paradoxically, accumulating evidence supports the view that core components of the cell cycle also play key roles in the development of terminally differentiated postmitotic neurons. Distinct cell cycle proteins including cell cycle-dependent kinases may contribute to naturally occurring programmed neuronal cell death in the developing mammalian brain. In addition, recent studies have uncovered a novel role for the cell cycle-associated ubiquitination machinery in the control of axonal growth and patterning in the developing brain. The underlying molecular mechanisms regulating these distinct cell cycle-based developmental events in neurons are just beginning to be understood.     

Cell cycle re-entry mechanisms after DNA damage checkpoints: Giving it some gas to shut off the breaks!

In order to maintain genetic integrity, cells are equipped with cell cycle checkpoints that detect DNA damage, orchestrate repair, and if necessary, eliminate severely damaged cells by inducing apoptotic cell death. The mitotic machinery is now emerging as an important determinant of the cellular responses to DNA damage where it functions as both the downstream target and the upstream regulator of the G2/M checkpoint. Cell cycle kinases and the DNA damage checkpoint kinases appear to reciprocally control each other. Specifically, cell cycle kinases control the inactivation of DNA damage checkpoint signaling. Termination of a DNA damage response by mitotic kinases appears to be an evolutionary conserved mechanism that allows resumption of cell cycle progression. Here we review recent reports in which molecular mechanisms underlying checkpoint silencing at the G2/M transition are elucidated.     

The coupling of cell growth to the cell cycle

The development of a complex multicellular organism requires a coordination of growth and cell division under the control of patterning mechanisms. Studies in yeast have pioneered our understanding of the relationship between growth and cell division. In recent years, many of the pathways that regulate growth in multicellular eukaryotes have been identified. This work has revealed interesting and unexpected relationships between mechanisms that regulate growth and the cell cycle machinery.     

Divide and differentiate

The elegant choreography of metazoan development demands exquisite regulation of cell-division timing, orientation, and asymmetry. In this review, we discuss studies in Drosophila and C. elegans that reveal how the cell cycle machinery, comprised of cyclin-dependent kinase (CDK) and cyclins functions as a master regulator of development. We provide examples of how CDK/cyclins: (1) regulate the asymmetric localization and timely destruction of cell fate determinants; (2) couple signaling to the control of cell division orientation; and (3) maintain mitotic zones for stem cell proliferation. These studies illustrate how the core cell cycle machinery should be viewed not merely as an engine that drives the cell cycle forward, but rather as a dynamic regulator that integrates the cell-division cycle with cellular differentiation, ensuring the coherent and faithful execution of developmental programs.     

Cell cycle machinery and stroke

Stroke results from a transient or permanent reduction in blood flow to the brain. The mechanisms involving neuronal death following ischemic insult are complex and not fully understood. One signal which may control ischemic neuronal death is the inappropriate activation of cell cycle regulators including cyclins, cyclin dependent kinases (CDKs) and endogenous cyclin dependent kinase inhibitors (CDKIs). In dividing cells, activation of cell cycle machinery induces cell proliferation. In the context of terminally differentiated-neurons, however, aberrant activation of these elements triggers neuronal death. Indeed, there are several lines of correlative and functional evidence supporting this "cell cycle/neuronal death hypothesis". The objective of this review is to summarize the findings implicating cell cycle machinery in ischemic neuronal death from in vitro and in vivo studies. Importantly, determining and blocking the signaling pathway(s) by which these molecules act to mediate ischemic neuronal death, in conjunction with other targets may provide a viable therapeutic strategy for stroke damage.     

Engagement of DYRK2 in proper control for cell division

Dysregulation of cell cycle machinery causes abnormal cell division, leading to cancer development. To drive cell cycle properly, expression levels of cell cycle regulators are tightly regulated through the cell cycle. Dual specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2) is a Ser/Thr kinase, and its intracellular functions had not been elucidated for decades. Recent studies have shown that DYRK2 down-regulates key molecules on cell cycle control. This review mainly highlights the DYRK2 function during cell division. In addition, we summarize tumor suppressive role of DYRK2 in cancer cells and discuss future research directions for DYRK2 toward the novel cancer therapies.     

The long noncoding RNA Vax2os1 controls the cell cycle progression of photoreceptor progenitors in the mouse retina

Long noncoding RNAs (lncRNAs) are emerging as regulators of many basic cellular pathways. Several lncRNAs are selectively expressed in the developing retina, although little is known about their functional role in this tissue. Vax2os1 is a retina-specific lncRNA whose expression is restricted to the mouse ventral retina. Here we demonstrate that spatiotemporal misexpression of Vax2os1 determines cell cycle alterations in photoreceptor progenitor cells. In particular, the overexpression of Vax2os1 in the developing early postnatal mouse retina causes an impaired cell cycle progression of photoreceptor progenitors toward their final committed fate and a consequent delay of their differentiation processes. At later developmental stages, this perturbation is accompanied by an increase of apoptotic events in the photoreceptor cell layer, in comparison with control retinas, without affecting the proper cell layering in the adult retina. Similar results are observed in mouse photoreceptor-derived 661W cells in which Vax2os1 overexpression results in an impairment of the cell cycle progression rate and cell differentiation. Based on these results, we conclude that Vax2os1 is involved in the control of cell cycle progression of photoreceptor progenitor cells in the ventral retina. Therefore, we propose Vax2os1 as the first example of lncRNA that acts as a cell cycle regulator in the mammalian retina during development.