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.     

THE CIRCADIAN CLOCK GENE PER1 SUPPRESSES CANCER CELL PROLIFERATION AND TUMOR GROWTH AT SPECIFIC TIMES OF DAY

Cell cycle progression is tightly regulated. The expressions of cell cycle regulators, the products of which either promote or inhibit cell proliferation, oscillate during each cell cycle. Cellular proliferation and the expression of cell cycle regulators are also controlled by the circadian clock. Disruption of the circadian clock may thereby lead to deregulated cell proliferation. Mammalian Per2 is a core clock gene, the product of which suppresses cancer cell proliferation and tumor growth in vivo and in vitro. Because Per1, another key clock gene, is mutated in human breast cancers, and because its clock functions are similar and complementary to those of Per2, we have studied its role in modulating breast cancer cell proliferation and tumor growth. We find that breast cancer growth rate is gated by the circadian clock with two daily peaks and troughs, and that they are coupled to the daily expression patterns of clock-controlled genes that regulate cell proliferation. Down-regulation of the expression of tumor Per1 increases cancer cell growth in vitro and tumor growth in vivo by enhancing the circadian amplitude of the two daily tumor growth peaks. The data of the study suggest Per1 has tumor-suppressor function that diminishes cancer proliferation and tumor growth, but only at specific times of day. (Author correspondence: williamhrushesky@gmail.com).     

Embryonic expression patterns of the mouse and chick Gas1 genes

Control of cell proliferation is essential to generate the defined form of a multi-cellular organism. While much is known about the regulators for cell cycle progression, relatively little is known about the state of growth arrest. Growth arrest (G0) is defined as a cell in a metabolically active but proliferation-quiescent state (reviewed in Baserga (1985) The Biology of Cell Reproduction), typically induced by serum starvation in vitro. Using subtractive hybridization, Schneider et al. (Cell 54 (1988) 787) identified six genes (Gas1 through Gas6) whose expressions are upregulated in serum-deprived NIH3T3 cells. Among the Gas genes, Gas1 is the only one that can cause growth arrest when expressed in cultured cell (Cell 70 (1995) 595; Int. J. Cancer 9 (1998) 569). Here, we describe for the first time the expression pattern of Gas1 during mouse embryogenesis. Our data reveal that Gas1 is expressed in many regions that the cells are actively proliferating and suggest that it may have other roles during development than negatively regulating cell proliferation. Furthermore, we have cloned the chick GAS1 gene and documented the similarity and divergence of Gas1 gene expression patterns between the two species.     

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.     

FOXO转录因子调控哺乳动物的细胞周期和凋亡

细胞周期和细胞凋亡是哺乳动物细胞生命活动的两大关键事件。FOXO在哺乳动物的细胞分化、增殖、生长、衰老等生命活动中发挥着重要的调控作用,并且参与细胞周期和凋亡的调控,是细胞生死的开关,因此FOXO已成为肿瘤、癌症科学研究的热点之一。在机体细胞中,FOXO受到上游信号分子PI3K/PKB、Ras等的激活或抑制从而调节下游信号分子FasL、Bim、p27kip1、cyclinG2、cyclinB、p130、GADD45等,并与其他细胞周期调控因子形成复杂的信号网络,调节哺乳动物细胞周期的进程和凋亡事件。     

Global analysis of endothelial cell line proliferation patterns based on nutrient-depletion models: implications for a standardization of cell proliferation assays

It is known that cell populations growing in different environmental conditions may exhibit different proliferation patterns. However, it is not clear if, despite the diversity of the so-observed patterns, inherent cellular growth characteristics of the population can nevertheless be determined. This study quantifies the proliferative behaviour of the permanent endothelial human cell line, Eahy926, and establishes to which extent the estimation of the cell proliferation rate depends on variations of the experimental protocols. Cell proliferation curves were obtained for cells cultured over 16 days and the influences of cell seeding densities, foetal bovine serum content and frequency of culture medium changes were investigated. Quantitative dynamic modelling was conducted to evaluate the kinetic characteristics of this cell population. We proposed successive models and retained a nutrient-depletion toxicity dependant model, which takes into account the progressive depletion of nutrients, as well as the increase of toxicity in the cell culture medium. This model is shown to provide a very good and robust prediction of the experimental proliferation curves, whatever are the considered frequency of culture medium changes and serum concentrations. Thus, the model enables an intrinsic quantification of the parameters driving in vitro EAhy926 proliferation, including proliferation, nutrient consumption and toxicity increase rates, rather independently of the experiments design. We therefore propose that such models could provide a basis for a standardized quantification of intrinsic cell proliferation kinetics.     

A characterization of the effects of Dpp signaling on cell growth and proliferation in the Drosophila wing

Cell proliferation and patterning must be coordinated for the development of properly proportioned organs. If the same molecules were to control both processes, such coordination would be ensured. Here we address this possibility in the Drosophila wing using the Dpp signaling pathway. Previous studies have shown that Dpp forms a gradient along the AP axis that patterns the wing, that Dpp receptors are autonomously required for wing cell proliferation, and that ectopic expression of either Dpp or an activated Dpp receptor, Tkv(Q253D), causes overgrowth. We extend these findings with a detailed analysis of the effects of Dpp signaling on wing cell growth and proliferation. Increasing Dpp signaling by expressing Tkv(Q253D) accelerated wing cell growth and cell cycle progression in a coordinate and cell-autonomous manner. Conversely, autonomously inhibiting Dpp signaling using a pathway specific inhibitor, Dad, or a mutation in tkv, slowed wing cell growth and division, also in a coordinate fashion. Stimulation of cell cycle progression by Tkv(Q253D) was blocked by the cell cycle inhibitor RBF, and required normal activity of the growth effector, PI3K. Among the known Dpp targets, vestigial was the only one tested that was required for Tkv(Q253D)-induced growth. The growth response to altering Dpp signaling varied regionally and temporally in the wing disc, indicating that other patterned factors modify the response.     

Bud-Localization of CLB2 mRNA Can Constitute a Growth Rate Dependent Daughter Sizer

Maintenance of cellular size is a fundamental systems level process that requires balancing of cell growth with proliferation. This is achieved via the cell division cycle, which is driven by the sequential accumulation and destruction of cyclins. The regulatory network around these cyclins, particularly in G₁, has been interpreted as a size control network in budding yeast, and cell size as being decisive for the START transition. However, it is not clear why disruptions in the G₁ network may lead to altered size rather than loss of size control, or why the S-G₂-M duration also depends on nutrients. With a mathematical population model comprised of individually growing cells, we show that cyclin translation would suffice to explain the observed growth rate dependence of cell volume at START. Moreover, we assess the impact of the observed bud-localisation of the G₂ cyclin CLB2 mRNA, and find that localised cyclin translation could provide an efficient mechanism for measuring the biosynthetic capacity in specific compartments: The mother in G₁, and the growing bud in G₂. Hence, iteration of the same principle can ensure that the mother cell is strong enough to grow a bud, and that the bud is strong enough for independent life. Cell sizes emerge in the model, which predicts that a single CDK-cyclin pair per growth phase suffices for size control in budding yeast, despite the necessity of the cell cycle network around the cyclins to integrate other cues. Size control seems to be exerted twice, where the G₂/M control affects bud size through bud-localized translation of CLB2 mRNA, explaining the dependence of the S-G₂-M duration on nutrients. Taken together, our findings suggest that cell size is an emergent rather than a regulatory property of the network linking growth and proliferation.     

Cell cycle control in the Drosophila wing

How Wingless and Decapentaplegic regulate cell proliferation in the developing Drosophila limbs and how cell proliferation and limb growth are coordinated are two of the most intriguing questions in developmental biology nowadays. Two recent reports [Johnston LA, Edgar BA. Nature 1998;394:82-84 (Ref. 1) and Neufeld TP, et al. 1998; Cell 93:1183-1193 (Ref. 2)] have shed new light on these questions. The first report [Johnston LA, Edgar BA. Nature 1998;394:82-84 (Ref. 1)] shows how Wingless regulates the cell cycle of a particular group of cells in the late wing discs. A second paper [Neufeld TP, et al. 1998; Cell 93:1183-1193 (Ref. 2)] shows the role of cell cycle regulators in proliferating wing disc cells and the relationship between cell division and limb growth.     

A mechanism of intracellular timing and its cooperation with extracellular signals in controlling cell proliferation and differentiation, an amended hypothesis.

Various observations suggest that an intracellular timer is involved in the control of cell proliferation and differentiation that supplements control by extracellular signaling and depends on quantitative relations between cytoplasm and nucleus. To further elucidate the mechanism of this timer, we examined the results of experiments with mice in which cell cycle regulating genes were inactivated: the inactivation of negative cell cycle regulators extends cell proliferation, whereas inactivation of positive regulators decreases cell proliferation. We conclude that this is caused in the former case by shortening of G1 which decreases the cytoplasmic growth rate per cell cycle, whereas in the latter case this rate is increased due to G1 prolongation. This is consistent with our hypothesis according to which the cytoplasmic/nuclear ratio must increase to a certain level to induce end stage differentiation and cell cycle arrest. A new basis of this hypothesis is the fact that end stage differentiation requires large quantities of membranous cytoplasmic structures that the cells are unable to produce de novo. Embryonic cells, however, possess only few of these structures. The only feasible way to multiply these structures is by growing more cytoplasm per cell cycle than needed for a doubling so that successively, the level of the cytoplasmic/nuclear ratio is reached that is required for differentiation. A consequence is that the cytoplasmic growth rate per cell cycle determines the number of amplification divisions. We suggest that the differentiation signal may be triggered when a differentiation-preventing protein (for example Bcl-2) is diluted out by the expansion of cytoplasmic membrane structures, thus simultaneously determining the cell size. The intracellular timer and extracellular signals cooperate in adjusting cell production to the organism's need and in determining when and how the cells respond to extracellular signals or transmit extracellular signals.     

Balance between cell division and differentiation during plant development

The processes which make possible that a cell gives rise to two daughter cells define the cell division cycle. In individual cells, this is strictly controlled both in time and space. In multicellular organisms extra layers of regulation impinge on the balance between cell proliferation and cell differentiation within particular ontogenic programs. In contrast to animals, organogenesis in plants is a post-embryonic process that requires developmentally programmed reversion of sets of cells from different differentiated states to a pluripotent state followed by regulated proliferation and progression through distinct differentiation patterns. This implies a fine coupling of cell division control, cell cycle arrest and reactivation, endoreplication and differentiation. The emerging view is that cell cycle regulators, in addition to controlling cell division, also function as targets for maintaining cell homeostasis during development. The mechanisms and cross talk among different cell cycle regulatory pathways are discussed here in the context of a developing plant.     

Modeling and computer simulations of tumor growth and tumor response to radiotherapy

A model of tumor growth and tumor response to radiation is introduced in which each tumor cell is taken into account individually. Each cell is assigned a set of radiobiological parameters, and the status of each cell is checked in discrete intervals. Tumor proliferation is governed by the cell cycle times of tumor cells, the growth fraction, the apoptotic capacity of the tumor, and the degree of tumor angiogenesis. The response of tumor cells to radiation is determined by the radiosensitivities and the oxygenation status. Computer simulation is performed on a 3D rigid cubic lattice, starting out from a single tumor cell. Random processes are simulated by Monte Carlo methods. Short cell cycle time, high growth fraction, and tumor angiogenesis all increase tumor proliferation rates. Accelerated time-dose patterns result in lower total doses needed for tumor control, but the extent of dose reduction depends on the kinetics and the radiosensitivities of tumor cells. Tumor angiogenesis alters fully oxygenated and hypoxic fractions within the tumor and subsequently affects the radiation response. It is demonstrated for selected radiobiological parameters that the simulation tools are suitable to quantitatively assess the total doses needed for tumor control. Using the simulation tools, it is feasible to simulate time-dependent effects during fractionated radiotherapy and to compare different time-dose patterns in terms of their tumor control.     

Ablation of cdk4 and cdk6 affects proliferation of basal progenitor cells in the developing dorsal and ventral forebrain

Little is known about the molecular players driving proliferation of neural progenitor cells (NPCs) during embryonic mouse development. Here, we demonstrate that proliferation of NPCs in the developing forebrain depends on a particular combination of cell cycle regulators. We have analyzed the requirements for members of the cyclin‐dependent kinase (cdk) family using cdk‐deficient mice. In the absence of either cdk4 or cdk6, which are both regulators of the G1 phase of the cell cycle, we found no significant effects on the proliferation rate of cortical progenitor cells. However, concomitant loss of cdk4 and cdk6 led to a drastic decrease in the proliferation rate of NPCs, specifically the basal progenitor cells of both the dorsal and ventral forebrain at embryonic day 13.5 (E13.5). Moreover, basal progenitors in the forebrain of Cdk4;Cdk6 double mutant mice exhibited altered cell cycle characteristics. Cdk4;cdk6 deficiency led to an increase in cell cycle length and cell cycle exit of mutant basal progenitor cells in comparison to controls. In contrast, concomitant ablation of cdk2 and cdk6 had no effect on the proliferation of NCPs. Together, our data demonstrate that the expansion of the basal progenitor pool in the developing telencephalon is dependent on the presence of distinct combinations of cdk molecules. Our results provide further evidence for differences in the regulation of proliferation between apical and basal progenitors during cortical development. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 660–670, 2018     

Metabolic control of the cell cycle

Cell division is a metabolically demanding process, requiring the production of large amounts of energy and biomass. Not surprisingly therefore, a cell''s decision to initiate division is co-determined by its metabolic status and the availability of nutrients. Emerging evidence reveals that metabolism is not only undergoing substantial changes during the cell cycle, but it is becoming equally clear that metabolism regulates cell cycle progression. Here, we overview the emerging role of those metabolic pathways that have been best characterized to change during or influence cell cycle progression. We then studied how Notch signaling, a key angiogenic pathway that inhibits endothelial cell (EC) proliferation, controls EC metabolism (glycolysis) during the cell cycle.     

Cell cycle regulation in the developing lens

Regulation of cell proliferation is a critical aspect of the development of multicellular organisms. The ocular lens is an excellent model system in which to unravel the mechanisms controlling cell proliferation during development. In recent years, several cell cycle regulators have been shown to be essential for maintaining normal patterns of lens cell proliferation. Additionally, many growth factor signaling pathways and cell adhesion factors have been shown to have the capacity to regulate lens cell proliferation. Given this complexity, understanding the cross talk between these many signaling pathways and how they are coordinated are important directions for the future.