Cell cycle regulators in cancer cell metabolism

Cancer proliferation and progression involves altered metabolic pathways as a result of continuous demand for energy and nutrients. In the last years, cell cycle regulators have been involved in the control of metabolic processes, such as glucose and insulin pathways and lipid synthesis, in addition to their canonical function controlling cell cycle progression. Here we describe recent data demonstrating the role of cell cycle regulators in the metabolic control especially in studies performed in cancer models. Moreover, we discuss the importance of these findings in the context of current cancer therapies to provide an overview of the relevance of targeting metabolism using inhibitors of the cell cycle regulation.     

Hormonal control of the plant cell cycle

Plant organogenesis is essentially a post-embryonic process that requires a strict balance between cell proliferation and differentiation. This is subject to a complex regulatory network which, in some cases, depends on the action of a variety of plant hormones. Of these, auxins and cytokinins are those best documented as impinging directly on cell cycle control. However, increasing evidence is accumulating to indicate that other hormones also have an impact on cell cycle control by influencing the availability of cell cycle regulators. In this article, we review the results that point to the variety of situations in which cell cycle progression is controlled by phytohormones.     

Control of cell proliferation during plant development

Knowledge of the control of cell division in eukaryotes has increased tremendously in recent years. The isolation and characterization of the major players from a number of systems and the study of their interactions have led to a comprehensive understanding of how the different components of the cell cycle apparatus are brought together and assembled in a fine-tuned machinery. Many parts of this machine are highly conserved in organisms as evolutionary distant as yeast and animals. Some key regulators of cell division have also been identified in higher plants and have been shown to be functional homologues of the yeast or animal proteins. Although still in its early days, investigations into the regulation of these molecules have provided some clues on how cell division is coupled to 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.     

14-3-3 proteins are involved in the regulation of mammalian cell proliferation

Summary. The 14-3-3 proteins are a family of abundant, widely expressed acidic polypeptides. The seven isoforms interact with over 70 different proteins. 14-3-3 isoforms have been demonstrated to be involved in the control of positive as well as negative regulators of mammalian cell proliferation. Here we used the approach of inactivating 14-3-3 protein functions via overexpression of dominant negative mutants to analyse the role of 14-3-3 proteins in mammalian cell proliferation. We found 14-3-3 dominant negative mutants to downregulate the proliferation rates of HeLa cells. Overexpression of these dominant negative mutants triggers upregulation of the protein levels of the cyclin-dependent kinase inhibitor p27, a major negative cell cycle regulator. In addition, they downregulate the protein levels of the important cell cycle promoter cyclin D1. These data provide new insights into mammalian cell proliferation control and allow a better understanding of the functions of 14-3-3 proteins.     

Developmental control of cell division patterns in the shoot apex

The shoot apical meristem is a group of rapidly dividing cells that generate all aerial parts of the plant. It is a highly organised structure, which can be divided into functionally distinct domains, characterised by specific proliferation rates of the individual cells. Genetic studies have enabled the identification of regulators of meristem function. These factors are involved in the formation and maintenance of the meristem, as well as in the formation of the primordia. Somehow, they must also govern cell proliferation rates within the shoot apex. Possible links between meristem regulators and the cell cycle machinery will be discussed. In order to analyse the role of cell proliferation in development, cell cycle gene expression has been perturbed using transgenic approaches and mutation. The effect of these alterations on growth and development at the shoot apex will be presented. Together, these studies give a first insight into the regulatory networks controlling the cell cycle and into the significance of cell proliferation in plant development.     

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.     

Engineering dynamic cell cycle control with synthetic small molecule-responsive RNA devices

Background

The cell cycle plays a key role in human health and disease, including development and cancer. The ability to easily and reversibly control the mammalian cell cycle could mean improved cellular reprogramming, better tools for studying cancer, more efficient gene therapy, and improved heterologous protein production for medical or industrial applications.

Results

We engineered RNA-based control devices to provide specific and modular control of gene expression in response to exogenous inputs in living cells. Specifically, we identified key regulatory nodes that arrest U2-OS cells in the G0/1 or G2/M phases of the cycle. We then optimized the most promising key regulators and showed that, when these optimized regulators are placed under the control of a ribozyme switch, we can inducibly and reversibly arrest up to ~80 % of a cellular population in a chosen phase of the cell cycle. Characterization of the reliability of the final cell cycle controllers revealed that the G0/1 control device functions reproducibly over multiple experiments over several weeks.

Conclusions

To our knowledge, this is the first time synthetic RNA devices have been used to control the mammalian cell cycle. This RNA platform represents a general class of synthetic biology tools for modular, dynamic, and multi-output control over mammalian cells.

     

Role of Pin2/TRF1 in telomere maintenance and cell cycle control

Telomeres are specialized structures found at the extreme ends of chromosomes, which have many functions, including preserving genomic stability, maintaining cell proliferative capacity, and blocking the activation of DNA-damage cell cycle checkpoints. Deregulation of telomere length has been implicated in cancer and ageing. Telomere maintenance is tightly regulated by telomerase and many other telomere-associated proteins and is also closely linked to cell cycle control, especially mitotic regulation. However, little is known about the identity and function of the signaling molecules connecting telomere maintenance and cell cycle control. Pin2/TRF1 was originally identified as a protein bound to telomeric DNA (TRF1) and as a protein involved in mitotic regulation (Pin2). Pin2/TRF1 negatively regulates telomere length and importantly, its function is tightly regulated during the cell cycle, acting as an important regulator of mitosis. Recent identification of many Pin2/TRF1 upstream regulators and downstream targets has provided important clues to understanding the dual roles of Pin2/TRF1 in telomere maintenance and cell cycle control. These results have led us to propose that Pin2/TRF1 functions as a key molecule in connecting telomere maintenance and cell cycle control.     

Cell cycle and apoptosis

Apoptosis and proliferation are intimately coupled. Some cell cycle regulators can influence both cell division and programmed cell death. The linkage of cell cycle and apoptosis has been recognized for c-Myc, p53, pRb, Ras, PKA, PKC, Bcl-2, NF-kappa B, CDK, cyclins and CKI. This review summarizes the different functions of the proteins presently known to control both apoptosis and cell cycle progression. These proteins can influence apoptosis or proliferation but different variables, including cell type, cellular environment and genetic background, make it difficult to predict the outcome of cell proliferation, cell cycle arrest or cell death. These important decisions of cell proliferation or cell death are likely to be controlled by more than one signal and are necessary to ensure a proper cellular response.     

Drosophila neuroblast asymmetric divisions: cell cycle regulators, asymmetric protein localization, and tumorigenesis

Over the past decade, many of the key components of the genetic machinery that regulate the asymmetric division of Drosophila melanogaster neural progenitors, neuroblasts, have been identified and their functions elucidated. Studies over the past two years have shown that many of these identified components act to regulate the self-renewal versus differentiation decision and appear to function as tumor suppressors during larval nervous system development. In this paper, we highlight the growing number of molecules that are normally considered to be key regulators of cell cycle events/progression that have recently been shown to impinge on the neuroblast asymmetric division machinery to control asymmetric protein localization and/or the decision to self-renew or differentiate.