Flexibility exists in the region of [A6-A11, A7-B7] disulfide bonds during insulin precursor folding

Programmed cell death or apoptosis is the regulatory mechanism for removing unneeded cells during animal development and in tissue homeostasis. Perturbation of the cell death mechanisms leads to various disorders, including neurodegenerative diseases, immunodeficiency diseases, and tumors. c-Jun N-terminal kinase (JNK) has crucial roles in the regulation of cell death in response to many stimuli. Since JNK is highly conserved from yeast to mammals, genetic studies using model animals are helpful in understanding the principal cell death mechanisms regulated by JNK. For example, loss-of-function studies using the targeted disruption of murine genes have established the genetic framework of the mechanisms of the cell death induced by UV radiation. Also, in Drosophila, many cell death-related genes have been identified by genetics. Genetic studies of JNK-dependent cell death mechanisms should shed light on the regulation of both physiological and pathological cell death.     

Phosphorylation-mediated regulation of GEFs for RhoA

Spatio-temporal control of RhoA GTPase is critical for regulation of cell migration, attachment to extracellular matrix, and cell–cell adhesions. Activation of RhoA is mediated by guanine nucleotide exchange factors (GEFs), a diverse family of enzymes that are controlled by multiple signaling pathways regulating actin cytoskeleton and cell migration. GEFs can be regulated by different mechanisms. Growing evidence demonstrates that phosphorylation serves as one of the predominant signals controlling activity, interactions, and localization of RhoGEFs. It acts as a positive and a negative regulator, and allows for regulation of RhoGEFs by multiple signaling cascades. Although there are common trends in phosphorylation-mediated regulation of some RhoGEF homologs, the majority of GEFs utilize distinct mechanisms that are dictated by their unique structure and interaction networks. This diversity enables multiple signaling pathways to use different RhoGEFs for regulation of a single central—RhoA. Here, we review current examples of phosphorylation-mediated regulation of GEFs for RhoA and its role in cell migration, discuss mechanisms, and provide insights into potential future directions.     

Mathematical models of cell cycle regulation

The cell division cycle is a fundamental process of cell biology and a detailed understanding of its function, regulation and other underlying mechanisms is critical to many applications in biotechnology and medicine. Since a comprehensive analysis of the molecular mechanisms involved is too complex to be performed intuitively, mathematical and computational modelling techniques are essential. This paper is a review and analysis of recent approaches attempting to model cell cycle regulation by means of protein-protein interaction networks.     

Modeling the effect of deregulated proliferation and apoptosis on the growth dynamics of epithelial cell populations in vitro

We present a three-dimensional individual cell-based, biophysical model to study the effect of normal and malfunctioning growth regulation and control on the spatial-temporal organization of growing cell populations in vitro. The model includes explicit representations of typical epithelial cell growth regulation and control mechanisms, namely 1), a cell-cell contact-mediated form of growth inhibition; 2), a cell-substrate contact-dependent cell-cycle arrest; and 3), a cell-substrate contact-dependent programmed cell death (anoikis). The model cells are characterized by experimentally accessible biomechanical and cell-biological parameters. First, we study by variation of these cell-specific parameters which of them affect the macroscopic morphology and growth kinetics of a cell population within the initial expanding phase. Second, we apply selective knockouts of growth regulation and control mechanisms to investigate how the different mechanisms collectively act together. Thereby our simulation studies cover the growth behavior of epithelial cell populations ranging from undifferentiated stem cell populations via transformed variants up to tumor cell lines in vitro. We find that the cell-specific parameters, and in particular the strength of the cell-substrate anchorage, have a significant impact on the population morphology. Furthermore, they control the efficacy of the growth regulation and control mechanisms, and consequently tune the transition from controlled to uncontrolled growth that is induced by the failures of these mechanisms. Interestingly, however, we find the qualitative and quantitative growth kinetics to be remarkably robust against variations of cell-specific parameters. We compare our simulation results with experimental findings on a number of epithelial and tumor cell populations and suggest in vitro experiments to test our model predictions.     

The control of body size in insects

Control mechanisms that regulate body size and tissue size have been sought at both the cellular and organismal level. Cell-level studies have revealed much about the control of cell growth and cell division, and how these processes are regulated by nutrition. Insulin signaling is the key mediator between nutrition and the growth of internal organs, such as imaginal disks, and is required for the normal proportional growth of the body and its various parts. The insulin-related peptides of insects do not appear to control growth by themselves, but act in conjunction with other hormones and signaling molecules, such as ecdysone and IDGFs. Size regulation cannot be understood solely on the basis of the mechanisms that control cell size and cell number. Size regulation requires mechanisms that gather information on a scale appropriate to the tissue or organ being regulated. A new model mechanism, using autocrine signaling, is outlined by which tissue and organ size regulation can be achieved. Body size regulation likewise requires a mechanism that integrates information at an appropriate scale. In insects, this mechanism operates by controlling the secretion of ecdysone, which is the signal that terminates the growth phase of development. The mechanisms for size assessment and the pathways by which they trigger ecdysone secretion are diverse and can be complex. The ways in which these higher-level regulatory mechanisms interact with cell- and molecular- level mechanisms are beginning to be elucidated.     

Perspectives in the coordinate regulation of cell cycle events in Synechococcus

The concepts of cell theory and the notions of coordinate regulation of the cell cycle have been known for centuries but the conundrum of coordinate regulation of the cell cycle remains to be resolved. The unique characteristics of the cell division cycle of Synechococcus, a photosynthetic bacterium, suggest the existence of a complex network of light/dark responsive gene regulatory factors that coordinate its cell cycle events. Evaluation of the highly ordered cell cycle of Synechococcus led to the construction of workable models that coordinate the cell cycle events. A central issue in bacterial cell growth is the elucidation of the genetic regulatory mechanisms that coordinate the cell cycle events. Synechococcus, a unicellular cyanobacterium, displays a peculiar cell growth cycle. In the light growth conditions, a highly ordered and sequentially coordinated appearances of r-protein synthesis, rRNA synthesis, DNA replication, chromosome segregation, and cell septum formation occur (Figs 1, 2A). Cell membrane syntheses occur predominantly during mid-cell cycle and cell division period. Synthesis of thylakoid (=photosynthetic apparatus) is thought to occur during mid-cell cycle and coincides with a period of peak phospholipid synthesis and oxygen production (Csatorday and Horvath, 1977; Asato, 1979). Cell wall syntheses occur in short discontinuous periods throughout the cell cycle and during cell division (Asato, 1984). Distinct D1 (=G1), C (S) and D2 (=G2) periods as defined by Cooper and Helmstetter (1968) are observed in synchronized cultures of Synechococcus (Asato, 1979). When light grown cultures are placed in the dark, the ongoing cell cycles are aborted in the dark (Fig. 3A) and cell divisions do not occur (Asato, 1983; Marino and Asato, 1986). Upon re-exposure of the cell cultures to the light growth conditions, about 14 h later, new cell cycles are re-initiated. These characteristics of cell growth are considered to be expressions of a unique strategy of obligate phototrophic mode of growth to perpetuate their species (Asato, 2003). Nevertheless, the intermediate metabolism, the synthesis of building block molecules, the genetics and molecular biology in the formation of major macromolecules are similarto heterotrophs such as E. coli. In any case, the genes that are involved in the formation of the cellular structures and the genes that control the orderly appearances of the cell cycle events must be coordinated by novel genetic mechanisms. Currently, there are no known physiological/physical mechanisms, growth rate dependent factors or traditional genetic regulatory mechanisms that could explain the coordinate regulation of the cell cycle events in bacteria (Newton and Ohta, 1992; Vinella and D'Ari, 1995; Donachie, 2001; Margolin and Bernander, 2004). Because the genetic mechanisms of coordinate regulation of cell cycle events in bacteria are largely unexplained, the questions on how Synechococcus coordinates the cell cycle events present a difficult problem to resolve. Nevertheless, the problems with regard to the coordinate regulation of the cell cycle events of Synechococcus must be considered. Possible solutions are developed and described in this article. The proposed schemes do not exclude the formation of other genetic mechanisms on the regulation of cell cycle events in Synechococcus. Although the cell cycle of Synechococcus is not widely known, the issues on the coordinate regulation of the cell cycle events are not trivial since similar regulatory mechanisms most likely occur in other prokaryotes.     

Interactions between the developmental program and cell cycle regulation of Aspergillus nidulans

Aspergillus nidulans is a multicellular fungus being used to study developmental regulation and cell cycle regulation. Genetic and molecular mechanisms underlying both processes have been characterized. Two types of observations suggest that there is significant interaction between cell cycle and developmental regulatory mechanisms. First, A. nidulans development involves the formation of specialized cell types that contain different, but specific, numbers of nuclei that are differentially regulated for cell cycle progression. Second, mutations directly affecting nuclear division can have major affects on cell differentiation during development. In this essay we describe these interactions and point out potential mechanisms for the cross talk between morphogenesis and the cell cycle that are tractable for future experimental investigation.     

Ion channels and transporters involved in cell volume regulation and sensor mechanisms

All animal cell types have an appropriate volume. Even under physiological conditions of constant extracellular osmolarity, cells must regulate their volume. Cell volume is subjected to alterations because of persistent physicochemical osmotic load resulting from Donnan-type colloid osmotic pressure and of cell activity-associated changes in intracellular osmolarity resulting from osmolyte transport and metabolism. The strategy adopted by animal cells for coping with volume regulation on osmotic perturbation is to activate transport pathways, including channels and transporters, mainly for inorganic osmolytes to drive water flow. Under normotonic conditions, cells undergo volume regulation by pump-mediated mechanisms. Under anisotonic conditions, volume regulation occurs by additional channel/transporter-mediated mechanisms. Cell volume regulation is also attained through adjustment of intracellular levels not only of inorganic but also of organic osmolytes with changing the expression of their transporters or regulation of metabolism. In cell volume regulation mechanism, several "volume sensors" are thought to be involved. A volume-sensitive Cl- channel has lately attracted considerable attention in this regard.     

The complex nature of protein phosphatases

Protein phosphatases are integrally associated with the regulation of cellular signaling. The mechanisms underlying the specific regulatory roles are likely to be unique to each cell system. Nevertheless, analysis of phosphatase regulation in a number of systems has identified phosphatase targeting through association with a wide range of binding partners to be a fundamental mechanism of regulation. Using protein phosphatase 2A (PP2A) as an example, this snapshot summarizes these fundamental mechanisms of protein phosphatase regulation.     

INSISTC: Incorporating network structure information for single-cell type classification

Uncovering gene regulatory mechanisms in individual cells can provide insight into cell heterogeneity and function. Recent accumulated Single-Cell RNA-Seq data have made it possible to analyze gene regulation at single-cell resolution. Understanding cell-type-specific gene regulation can assist in more accurate cell type and state identification. Computational approaches utilizing such relationships are under development. Methods pioneering in integrating gene regulatory mechanism discovery with cell-type classification encounter challenges such as determine gene regulatory relationships and incorporate gene regulatory network structure. To fill this gap, we developed INSISTC, a computational method to incorporate gene regulatory network structure information for single-cell type classification. INSISTC is capable of identifying cell-type-specific gene regulatory mechanisms while performing single-cell type classification. INSISTC demonstrated its accuracy in cell type classification and its potential for providing insight into molecular mechanisms specific to individual cells. In comparison with the alternative methods, INSISTC demonstrated its complementary performance for gene regulation interpretation.     

Epigenetic regulation in adult stem cells and cancers

Adult stem cells maintain tissue homeostasis by their ability to both self-renew and differentiate to distinct cell types. Multiple signaling pathways have been shown to play essential roles as extrinsic cues in maintaining adult stem cell identity and activity. Recent studies also show dynamic regulation by epigenetic mechanisms as intrinsic factors in multiple adult stem cell lineages. Emerging evidence demonstrates intimate crosstalk between these two mechanisms. Misregulation of adult stem cell activity could lead to tumorigenesis, and it has been proposed that cancer stem cells may be responsible for tumor growth and metastasis. However, it is unclear whether cancer stem cells share commonalities with normal adult stem cells. In this review, we will focus on recent discoveries of epigenetic regulation in multiple adult stem cell lineages. We will also discuss how epigenetic mechanisms regulate cancer stem cell activity and probe the common and different features between cancer stem cells and normal adult stem cells.     

Maintaining tissue homeostasis: dynamic control of somatic stem cell activity

Long-term maintenance of tissue homeostasis relies on the accurate regulation of somatic stem cell activity. Somatic stem cells have to respond to tissue damage and proliferate according to tissue requirements while avoiding overproliferation. The regulatory mechanisms involved in these responses are now being unraveled in the intestinal epithelium of Drosophila, providing new insight into strategies and mechanisms of stem cell regulation in barrier epithelia. Here, we review these studies and highlight recent findings in vertebrate epithelia that indicate significant conservation of regenerative strategies between vertebrate and fly epithelia.     

The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility

Cell migration is a complex process requiring tight control of several mechanisms including dynamic reorganization of the actin cytoskeleton and adhesion to the extracellular matrix. The GPI-anchored urokinase plasminogen activator receptor (uPAR) has an important role in the regulation of cell motility in many cell types. This is partly due to the localization of proteolytic activity on the cell surface by binding of the serine protease uPA. Results accumulated over the last decade suggest that uPAR is also involved in motility control through other mechanisms. These include induction of signal transduction events after ligation with uPA, binding to the extracellular matrix molecule vitronectin (VN), and association with integrins and other transmembrane partners. In this review these mechanisms will be discussed with a special emphasis on how the GPI-linked receptor transmits signals to the intracellular milieu and how uPAR participates in the regulation of actin cytoskeleton reorganization and cell adhesion during cell migration.     

The mechanism of leaf morphogenesis

Whether cell division is a driving force in plant morphogenesis has long been debated. In this review, the evidence for the existence of cell division-dependent and cell division-independent mechanisms of plant morphogenesis is discussed. The potential mechanisms themselves are then analysed, as is our understanding of the regulation of these mechanisms and how they are integrated into development, with particular emphasis on data arising from the investigation of leaf morphogenesis. The analysis indicates the existence of both cell division-dependent and cell division-independent mechanisms in leaf morphogenesis and highlights the importance of future investigations to unravel the co-ordination of these mechanisms.     

Epigenome-Metabolome-Epigenome signaling cascade in cell biological processes

Cell fate determination as a fundamental question in cell biology has been extensively studied at different regulatory levels for many years. However, the mechanisms of multilevel regulation of cell fate determination remain unclear. Recently, we have proposed an Epigenome-Metabolome-Epigenome (E-M-E) signaling cascade model to describe the cross-over cooperation during mouse somatic cell reprogramming. In this review, we summarize the broad roles of E-M-E signaling cascade in different cell biological processes, including cell differentiation and dedifferentiation, cell specialization, cell proliferation, and cell pathologic processes. Precise E-M-E signaling cascades are critical in these cell biological processes, and it is of worth to explore each step of E-M-E signaling cascade. E-M-E signaling cascade model sheds light on and may open a window to explore the mechanisms of multilevel regulation of cell biological processes.