The closely related debates concerning abortion, the protection of the embryo and stem cell science have captured the legislative agenda in Mexico in recent years. This paper examines some contemporary debates related to stem cell science and the legal and political action that has followed in the wake of the latest Supreme Court judgment on abortion, which debates are directly linked to the degrees of protection of the embryo stipulated in the Mexican Constitution. While some Mexican states have (...) opted to take no further action, others, where conservative political forces are in the majority, have been very active in seeking to ensure that their constitutions are amended to protect human life from conception onwards. This intense legislative activity has not, however, been repeated at the federal level, where there is currently no overarching national regulatory framework governing stem cell research. Although major efforts have been made by the conservative block within the Senate to bring forward legislative proposals for the prohibition of human embryonic stem cell research, and despite the public expression by the federal government of its commitment to encourage inward investment and innovation in the area of biotechnology, stem cell science has, so far, remained unregulated. The legislative challenge is to resist the pressure that has been injected by religious leaders and to act in accordance with the values and principles adopted by the community in the Mexican Constitution. In the final analysis, Mexico faces particular difficulties in accommodating conservative political forces on one hand, while recognising on the other its need, as an emerging economy, to promote a progressive approach to innovation in biotechnology. (shrink)

ABSTRACT In this paper I argue that liberal democratic communities are justified in regulating the activities of their members because of the inevitable existence of conflicting conceptions of what is considered as morally right. This will often lead to tension and disputes, and in such circumstances, reliance on peaceful or orderly co‐existence will not normally suffice. In such pluralistic societies, the boundary between permissible and impermissible activities will be unclear; and this becomes a particular concern in controversial issues which raise (...) specific anxieties and uncertainty. One context that has repeatedly raised issues in this regard is that of biotechnology and, in particular, the recent stem cell debate, on which this paper concentrates. While such developments have the potential to make significant improvements to therapeutic progress, we should also be sceptical because predicting the impact of these developments remains uncertain and complex. For the sake of socio‐political stability, it will therefore be necessary to enact and enforce rules which limit these competing claims in public policy but which may not be compatible with what individual moral commitments ideally permit. One way to achieve this is to establish procedural frameworks to resolve potential disputes in the public sphere about what is right, wrong, or permissible conduct. I argue that for one to commit to authoritative regulation, an idea of harm prevention through state intervention is necessary; and that this requires optimum mechanisms of procedure which allow the individual the opportunity to compromise and yet to continue to oppose or fight for changes as demanded by his or her moral position. (shrink)

In this paper I argue that liberal democratic communities are justified in regulating the activities of their members because of the inevitable existence of conflicting conceptions of what is considered as morally right. This will often lead to tension and disputes, and in such circumstances, reliance on peaceful or orderly co‐existence will not normally suffice. In such pluralistic societies, the boundary between permissible and impermissible activities will be unclear; and this becomes a particular concern in controversial issues which raise specific (...) anxieties and uncertainty. One context that has repeatedly raised issues in this regard is that of biotechnology and, in particular, the recent stem cell debate, on which this paper concentrates. While such developments have the potential to make significant improvements to therapeutic progress, we should also be sceptical because predicting the impact of these developments remains uncertain and complex.For the sake of socio‐political stability, it will therefore be necessary to enact and enforce rules which limit these competing claims in public policy but which may not be compatible with what individual moral commitments ideally permit. One way to achieve this is to establish procedural frameworks to resolve potential disputes in the public sphere about what is right, wrong, or permissible conduct. I argue that for one to commit to authoritative regulation, an idea of harm prevention through state intervention is necessary; and that this requires optimum mechanisms of procedure which allow the individual the opportunity to compromise and yet to continue to oppose or fight for changes as demanded by his or her moral position. (shrink)

Stem cell technology is an emerging science field; it is the unique regenerative ability of the pluripotent stem cell which scientists hope would be effective in treating various medical conditions. While it has gained significant advances in research, it is a sensitive subject involving human embryo destruction and human experimentation, which compel governments worldwide to ensure that the related procedures and experiments are conducted ethically. Based on face-to-face interviews with selected Malaysian ethicists, scientists and policymakers, the objectives and (...) effectiveness of the current Guideline for Stem Cell Research and Therapy are examined. The study’s findings show that the guideline is rather ineffective in ensuring good ethical governance of the technology. A greater extent of unethical conduct is likely present in the private medical clinics or laboratories offering stem cell therapies compared with the public medical institutions providing similar services, as the latter are closely monitored by the governmental agencies enforcing the relevant policies and laws. To address concerns over malpractices or unethical conduct, this paper recommends a comprehensive revision of the current stem cell guideline so that adequate provisions exist to regulate the explicit practices of the private and public stem cell sectors, including false advertising and accountability. The newly revised Malaysian stem cell guideline will align with the Guidelines for Stem Cell Research and Clinical Translation of the International Society for Stem Cell Research containing secular but universal moral rules. However, a regulatory policy formulated to govern the technology remains the main thrust of empowering the guideline for compliance among the stakeholders. (shrink)

The emergence of a new tissue economy raises issues for the governance of risk and concepts of the body and self. This article explores the development of autologous cell therapies as a form of tissue engineering and considers how and why autologous applications are seen as less risky and more socially and politically acceptable. In a careful analysis of contemporary debates around the need for new international policies to regulate these technologies, we critically assess the discursive strategies employed to (...) support ideas of the body as a natural entity. Central to these debates are assumptions that autologous applications do not threaten the moral or corporeal integrity of the individual and that they are ‘an ethics-free zone’. Analysis reveals that concepts such as intercorporeality need to be refined if they are to assist our understanding of these cell-based therapies. We consider the biopolitics of Autologous Chondrocyte Implantation (ACI) in order to show the linkages between the culturing of cells, regulation and the reproduction of the self. (shrink)

Regulation of the cytoplasmic stability of mRNAs has recetly been identified as a major control mechanism which governs mRNA levels in a variety of eukaryotic systems. In this review we discuss what is known about several experimental systems that exhibit regulated mRNA stability, describe the mechanisms that cells may use to achieve control of mRNA degradation, and suggest areas of future investigation likely to provide new insights into this process.

Mast cells are a unique class of blood cell. Unlike most blood cells, undifferentiated precursors of mast cells migrate in the bloodstream, invade tissues, proliferate there and then differentiate. Even after differentiation, some mast cells may proliferate extensively. Differentiation of mast cells is regulated by both diffusible growth factors and direct contact with fibroblasts.

Stem cell research is a newly emerging technology that promises a wide variety of benefits for humanity. It has, however, also caused much ethical, legal, and theological debate. While some forms of its application were prohibited in the beginning, they have now started to be used in many countries. This fact obliges us to discuss the regulation of stem cell research at national and international level. It is obvious that in order to make regulations and to draw (...) up legislation at national or international levels it helps to know the perspectives of different cultures and faith traditions. In this article the issue is explored from an Islamic perspective. Firstly, some basic information is given about Islam to explain how laws are drawn up and regulations made in this tradition. Secondly, the principles on which the laws and regulations are based are applied to stem cell research, and finally the permitted and prohibited methods of stem cell research are described. The discussions throughout the paper demonstrate that while some ethicists argue that stem cell research is unethical in the Islamic tradition, tradition permits it as long as such research is aimed at improving human health. (shrink)

Development and maintenance of diverse organ systems require context‐specific regulation of stem cell behaviour. We hypothesize that this is achieved via reciprocal regulation between the cell cycle machinery and differentiation factors. This idea is supported by the parallel evolutionary emergence of differentiation pathways, cell cycle components and complex multicellularity. In addition, the activities of different cell cycle phases have been found to bias cells towards stem cell maintenance or differentiation. Finally, several direct mechanistic (...) links between these two processes have been established. Here, we focus on interactions between cyclin‐CDK complexes and differentiation regulators of the Notch pathway and Sox family of transcription factors within the context of pluripotent and neural stem cells. Thus, this hypothesis formalizes the links between these two processes as an integrated network. Since such factors are common to all stem cells, better understanding their interconnections will help to explain their behaviour in health and disease. (shrink)

The form of higher plants is largely dependent upon cell division and expansion patterns. Taking a genetic approach, Takahashi et al.(1) have identified a regulatory molecule in Arabidopsis thaliana called DIMINUTO (DIM), which is involved in determining the degree and direction of plant cell expansion. Their extensive characterization of a dim mutant suggested a direct involvement of the DIM gene in regulating cell elongation, perhaps by modulating the expression of structural genes which determine the orientation and elasticity (...) of the cell wall. (shrink)

Ribosomal RNA transcription was one of the first model systems for molecular characterization of a transcription regulatory mechanism and certainly one of the best studied in the widest range of organisms. In multicellular organisms, however, the issue of cell‐type‐specific regulation of rRNA transcription has not been well addressed. Here I propose that a systematic study of cell‐type‐specific regulation of rRNA transcription may reveal new regulatory mechanisms that have not been previously realized. Specifically, issues concerning the (...) class='Hi'>cell‐type‐specific requirement for rRNA production, the universality of Pol I transcription complex and the division of rDNA into regulatory subdomains are discussed. BioEssays 28: 719–725, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Most lymphocytes of the T cell lineage develop along the CD4/CD8 pathway and express antigen receptors on their surfaces consisting of clonotypic αβ chains associated with invariant CD3‐γδε components and ζ chains, collectively referred to as the T cell antigen receptor complex (TCR). Expression of the TCR complex is dynamically regulated during T cell development, with immature CD4+CD8+ thymocytes expressing only 10% of the number of αβ TCR complexes on their surfaces expressed by mature CD4+ and CD8+ (...) T cells. Recent evidence demonstrates that low surface TCR density on CD4+CD8+ thymocytes results from the limited survival of a single TCR component within the ER, the TCRα chain, which has a half life of only 15 minutes in immature thymocytes, compared to >75 minutes in mature T cells. Instability of TCRα proteins in immature CD4+CD8+ thymocytes represents a novel mechanism by which expression of the multisubunit TCR complex is quantitatively regulated during T cell development. In the current review we discuss our recent findings concerning the assembly, intracellular transport, and expression of αβ TCR complexes in CD4+CD8+ thymocytes and comment on the functional significance of TCRα instability during T cell development. (shrink)

Mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the tumor suppressor p53 directs the cellular response to cell cycle arrest, DNA repair, and cell survival, whereas upon severe damage, p53 drives the cell death response. One posttranslational modification of p53, phosphorylation at Serine 46, selectively occurs after severe DNA damage and is envisioned as a marker of the cell death (...) response. However, the molecular mechanism of action of the p53 Ser46 phospho‐isomer, the molecular timing of this phosphorylation event, and its activating effects on apoptosis and ferroptosis still await exploration. In this essay, the current body of evidence on the molecular function of this deadly p53 mark, its evolutionary conservation, and the regulation of the key players of this response, the p53 Serine 46 kinases, are reviewed and dissected. (shrink)

The calcium signals regulate the production and secretion of many signaling molecules like inositol trisphosphate ( $$IP_{3}$$ ) and adenosine triphosphate (ATP) in various cells including pancreatic $$\beta$$ -cells. The calcium signaling mechanisms regulating $$IP_{3}$$, ATP and insulin responsible for various functions of $$\beta$$ -cells are still not well understood. Any disturbance in these mechanisms can alter the functions of $$\beta$$ -cells leading to diabetes and metabolic disorders. Therefore, a mathematical model is proposed by incorporating the reaction-diffusion equation for calcium (...) dynamics and a system of first-order differential equations for $$IP_{3}$$, ATP-production and insulin secretion with initial and boundary conditions. The model incorporates the temporal dependence of $$IP_{3}$$ -production and degradation, ATP production and insulin secretion on calcium dynamics in a $$\beta$$ -cell. The piecewise linear finite element method has been used for the spatial dimension and the Crank-Nicolson scheme for the temporal dimension to obtain numerical results. The effect of changes in source influxes and buffers on calcium dynamics and production of $$IP_{3}$$, ATP and insulin levels in a $$\beta$$ -cell has been analyzed. It is concluded that the dysfunction of source influx and buffers can cause significant variations in calcium levels and dysregulation of $$IP_{3}$$, ATP and insulin production, which can lead to various metabolic disorders, diabetes, obesity, etc. The proposed model provides crucial information about the changes in mechanisms of calcium dynamics causing proportionate disturbances in $$IP_3$$, ATP and insulin levels in pancreatic cells, which can be helpful for devising protocols for diagnosis and treatment of various metabolic diseases. (shrink)

Regulation of stem cell research in Europe should not take place without public and scholarly inputThe European Union has, at present, no jurisdiction over research carried out in the member states, or concerning the “ethics” of member states. This does not, however, mean that decisions made by the European institutions cannot influence such matters greatly.There has recently been a lot of focus on the decision not to fund embryonic stem cell research during the first year of the (...) 6th framework programme , but behind the scenes a much more important and wide ranging set of regulations are being prepared.The European Commission has prepared a draft directive on setting standards of quality and safety for the donation, procurement, testing, processing, storage, and distribution of human tissues and cells.1 The purpose of this directive was originally to “ensure the quality and safety of human tissues and cells for clinical use” in the EU. This is clearly a laudable objective, fully in line with the EU’s jurisdiction in consumer protection and public health.During the intricate processes of political …. (shrink)

Interleukin‐1 receptor‐associated kinase‐1 (IRAK1) is linked to the pathogenesis of atherosclerosis; however, its role in macrophage foam cell formation is not known. Therefore, the present study investigated the role of IRAK1 in lipid uptake, biosynthesis, and efflux in THP‐1 derived macrophages and human monocyte‐derived macrophages (HMDMs). Ox‐LDL (40 μg/mL, 15 minutes–48 hours) treatment induced time‐dependent increase in IRAK1, IRAK4, and Stat1 activation in THP‐1 derived macrophages. IRAK1/4 inhibitor (INH) or IRAK1 siRNA significantly attenuated cholesterol accumulation, DiI‐Ox‐LDL binding, and uptake (...) while cholesterol efflux to apoAI and HDL was enhanced in THP‐1 derived macrophages and HMDMs. Ox‐LDL treatment significantly increased the mRNA expression of CD36, LOX‐1, SR‐A, ABCA1, ABCG1, Caveolin‐1, CYP27A1 while that of SR‐BI was decreased. IRAK1/4 inhibition or IRAK1 knockdown, however, attenuated Ox‐LDL‐induced CD36 expression; augmented ABCA1 and ABCG1 expression while expression of others was unaffected in THP‐1 derived macrophages and HMDMs. Moreover, IRAK1/4 inhibition had no significant effect on genes involved in lipid biosynthesis. In IRAK1/4 INH pre‐treated THP‐1 derived macrophages Ox‐LDL‐induced Stat1 phosphorylation and its binding to CD36 promoter was significantly attenuated while LXRα expression and its binding to the ABCA1/ABCG1 locus, NFATc2 activation and its binding to ABCA1 locus was enhanced. The present study thus demonstrates that IRAK regulates lipid accumulation by modulating CD36‐mediated uptake and ABCA1‐, ABCG1‐dependent cholesterol efflux. Therefore, IRAK1 can be a potential target for preventing macrophage foam cell formation. (shrink)

Protein secretion is conventionally viewed as taking place by either of two cellular routes, a regulated pathway, involving external stimuli and secretory granules, and a presumptive ‘constitutive’ pathway, which does not involve hormonal or neuronal stimuli or the production of secretory granules. The evidence reviewed here strongly suggests that there are post‐synthesis rate‐limiting steps for many proteins released by the ‘constitutive’ pathway and, hence, that regulation in some sense is involved here too. The nature of these rate‐limiting determinants and (...) events is discussed. (shrink)

It is a long-standing view that global translation varies during the cell cycle and is much lower in mitosis than in other cell-cycle phases. However, the central papers in the literature are not in agreement about the extent of downregulation in mitosis, ranging from a dramatic decrease to only a marginal reduction. Herein, it is argued that the discrepancy derives from technical challenges. Cell-cycle-dependent variations are most conveniently studied in synchronized cells, but the synchronization methods by themselves (...) often evoke stress responses that, in turn, affect translation rates. Further, it is argued that previously reported cell-cycle-dependent changes in the global translation rate to a large extent reflect responses to the synchronization methods. Recent findings strongly suggest that the global translation rate is not regulated in a cell-cycle-dependent manner. Novel techniques allowing a genome-wide analysis of translational profiles suggest that the extent and importance of selective translational regulation associated with cell-cycle transitions have been underestimated. Therefore, the main question is which messenger RNAs (mRNAs) are translated, rather than whether the global translation rate is decreased. (shrink)

Physiological concentrations of retinoic acid can induce acute alterations in the expression of the enzyme tissue transglutaminase in cultured macrophages. The induction of this enzyme offers a probe to study the mechanism of retinoid action in both normal and leukemic cells.

Emerging evidence suggests that microRNA (miRNA)‐mediated post‐transcriptional gene regulation plays an essential role in modulating embryonic stem (ES) cell pluripotency maintenance, differentiation, and reprogramming of somatic cells to an ES cell‐like state. Investigations from ES cell‐enriched miRNAs, such as mouse miR‐290 cluster and human miR‐302 cluster, and ES cell‐depleted miRNAs such as let‐7 family miRNAs, revealed a common theme that miRNAs target diverse cellular processes including cell cycle regulators, signaling pathway effectors, transcription factors, and (...) epigenetic modifiers and shape their protein output. The combinatorial effects downstream of miRNA action allow miRNAs to modulate cell‐fate decisions effectively. Furthermore, the transcription and biogenesis of miRNAs are also tightly regulated. Thus, elucidating the interplay between miRNAs and other modes of gene regulation will shed new light on the biology of pluripotent stem cells and somatic cell reprogramming. (shrink)

Physical forces regulate numerous biological processes during development, physiology, and pathology. Forces between the external environment and intracellular actin cytoskeleton are primarily transmitted through integrin‐containing focal adhesions and cadherin‐containing adherens junctions. Crosstalk between these complexes is well established and modulates the mechanical landscape of the cell. However, integrins and cadherins constitute large families of adhesion receptors and form multiple complexes by interacting with different ligands, adaptor proteins, and cytoskeletal filaments. Recent findings indicate that integrin‐containing hemidesmosomes oppose force transduction and (...) traction force generation by focal adhesions. The cytolinker plectin mediates this crosstalk by coupling intermediate filaments to the actin cytoskeleton. Similarly, cadherins in desmosomes might modulate force generation by adherens junctions. Moreover, mechanotransduction can be influenced by podosomes, clathrin lattices, and tetraspanin‐enriched microdomains. This review discusses mechanotransduction by multiple integrin‐ and cadherin‐based cell adhesion complexes, which together with the associated cytoskeleton form an integrated network that allows cells to sense, process, and respond to their physical environment. (shrink)

The transcription of rat prolactin and growth hormone genes in vitro requires a pituitary transcription factor, specific to certain cell types in the pituitary, which currently appears to be the PUF‐I/Pit‐1/GHF‐1 protein. This factor binds to cis‐regulatory elements in the 5′ region of both genes and exerts a positive influence on transcription initiation presumably by interacting with general transcription factors. The PUF‐I/Pit‐1/GHF‐1 transcriptional regulatory protein probably has an important role in not only the differentiation of the pituitary lactotroph/somatotroph (...) class='Hi'>cell lineage; it is also expressed in the early development of the nervous system but its function there is less well documented. It appears to be one member of a family of trans‐activator proteins involved in differential gene expression in several cell types. (shrink)

The expression of certain eukaryotic genes is – at least in part – controlled at the level of mRNA translation. The step of translational initiation represents the primary target for regulation. The regulation of the intracellular iron storage protein ferritin in response to iron levels provides a good example of translational control by a reversible RNA/protein interaction in the 5' untranslated region of an mRNA. We consider mechanisms by which mRNA/protein interactions may impede translation initiation and discuss recent (...) data suggesting that the ferritin example may represent the ‘tip of the iceberg’ of a more general theme for translational control. (shrink)

Despite recent progress in the identification of genes that regulate longevity, aging remains a mysterious process. One influential hypothesis is the idea that the potential for cell division and replacement are important factors in aging. In this work, we review and discuss this perspective in the context of interventions in mammals that appear to accelerate or retard aging. Rather than focus on molecular mechanisms, we interpret results from an integrative biology perspective of how gene products affect cellular functions, which (...) in turn impact on tissues and organisms. We review evidence suggesting that mutations that give rise to features resembling premature aging tend to be associated with cellular phenotypes such as increased apoptosis or premature replicative senescence. In contrast, many interventions in mice that extend lifespan and might delay aging, including caloric restriction, tend to either hinder apoptosis or result in smaller animals and thus may be the product of fewer cell divisions. Therefore, it appears plausible that changes in the number of times that cells, and particularly stem cells, divide during an organism's lifespan influence longevity and aging. We discuss possible mechanisms related to this hypothesis and propose experimental paradigms. BioEssays 30:567–578, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Ribonucleotide reductase (RNR) catalyzes the rate limiting step in the production of deoxyribonucleotides needed for DNA synthesis. In addition to the well documented allosteric regulation, the synthesis of the enzyme is also tightly regulated at the level of transcription. mRNAs for both subunits are cell cycle regulated and inducible by DNA damage in all organisms examined, including E. coli, S. cerevisiae and H. sapiens. This DNA damage regulation is thought to provide a metabolic state that facilitates DNA (...) replicational repair processes. S. cerevisiae also encodes a second large subunit gene, RNR3, that is expressed only in the presence of DNA damage. Genetic analysis of the DNA damage response in S. cerevisiae has shown that RNR expression is under both positive and negative control. Among mutants constitutive for RNR expression are the general transcriptional repression genes, SSN6 and TUP1. Mutations in POL1 and POL3 also activate RNR expression, indicating that the DNA damage sensory network may respond directly to blocks in DNA synthesis. A protein kinase, Dun1, has been identified that controls inducibility of RNR1, RNR2 and RNR3 in response to DNA damage and replication blocks. This result suggests that the RNR genes in S. cerevisiae form a regulon that is coordinately regulated by protein phosphorylation in response to DNA damage. (shrink)

The plasma membrane of polarized epithelial cells is divided into apical and basolateral surfaces, with different compositions. Proteins can be sent directly from the trans‐Golgi network (TGN) to either surface, or can be sent first to one surface and then transcytosed to the other. The glycosyl phosphatidylinositol anchor is a signal for apical targeting. Signals in the cytoplasmic domain containing a β‐turn determine basolateral targeting and retrieval, and are related to other sorting signals. Transcytosed proteins, such as the polymeric immunoglobulin (...) receptor (plgR), are endocytosed from the basolateral surface and then accumulate in a tubular compartment concentrated underneath the apical surface. This compartment, tentatively termed the apical recycling compartment, may be a central sorting station, as it apparently receives material from both surfaces and sorts them for delivery to the correct surface. Delivery to the apical surface from both the TGN and the apical recycling compartment appears to be regulated by protein kinases A and C, and endocytosis from the apical surface is also regulated by kinases. Transcytosis of the plgR is additionally regulated by phosphorylation of the plgR and by ligand binding to the plgR. Regulation of traffic in polarized epithelial cells plays a central role in cellular homeostasis, response to external signals and differentiation. (shrink)

Targeted transitions in chromatin states at thousands of genes are essential drivers of eukaryotic development. Therefore, understanding the in vivo dynamics of epigenetic regulators is crucial for deciphering the mechanisms underpinning cell fate decisions. This review illustrates how, in addition to its cell memory function, the Polycomb group of transcriptional regulators orchestrates temporal, cell and tissue‐specific expression of master genes during development. These highly sophisticated developmental transitions are dependent on the context‐ and tissue‐specific assembly of the different (...) types of Polycomb Group (PcG) complexes, which regulates their targeting and/or activities on chromatin. Here, an overview is provided of how PcG complexes function at multiple scales to regulate transcription, local chromatin environment, and higher order structures that support normal differentiation and are perturbed in tumorigenesis. (shrink)

Focal adhesions disassemble during mitosis, but surprisingly little is known about how these structures respond to other phases of the cell cycle. Three recent papers reveal unexpected results as they examine adhesions through the cell cycle. A biphasic response is detected where focal adhesions grow during S phase before disassembly begins early in G2. In M phase, activated integrins at the tips of retraction fibers anchor mitotic cells, but these adhesions lack the defining components of focal adhesions, such (...) as talin, paxillin, and zyxin. Re‐examining cell‐matrix adhesion reveals reticular adhesions, a new class of adhesion. These αVβ5 integrin‐mediated adhesions also lack conventional focal adhesion components and anchor mitotic cells to the extracellular matrix. As reviewed here, these studies present insight into how adhesion complexes vary through the cell cycle, and how unconventional adhesions maintain attachment during mitosis while providing spatial memory to guide daughter cell re‐spreading after cell division. (shrink)

The transcriptional profile of the entire Caulobacter crescentus genome over a synchronous cell cycle was recently described.(1) The analysis reveals a stunning 553 cell-cycle-regulated genes or orfs, nearly 19% of the genome, including putative functions in virtually all biological activities. Over a quarter of these genes/orfs respond to the Caulobacter master regulator, CtrA, most of them apparently indirectly. The analysis confirms and extends earlier observations showing that many proteins involved in cell cycle functions are expressed at the (...) cell age when they are needed. Conversely, the data suggest that proteins specifically expressed at a particular age may be involved in a process taking place then. BioEssays 23:563–565, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Rnd3/RhoE has two distinct functions, regulating the actin cytoskeleton and cell proliferation. This might explain why its expression is often altered in cancer and by multiple stimuli during development and disease. Rnd3 together with its relatives Rnd1 and Rnd2 are atypical members of the Rho GTPase family in that they do not hydrolyse GTP. Rnd3 and Rnd1 both antagonise RhoA/ROCK‐mediated actomyosin contractility, thereby regulating cell migration, smooth muscle contractility and neurite extension. In addition, Rnd3 has been shown to (...) have a separate role in inhibiting cell cycle progression by reducing translation of cell cycle regulators, including cyclin D1 and Myc. We propose that Rnd3 could act as a tumour suppressor to limit proliferation, but when mutations bypass this activity of Rnd3, it can promote cancer invasion through its effects in the actin cytoskeleton. (shrink)

It has generally been observed that cells grow to a certain size before they divide. In the last few years, the PI3K signal transduction pathway has emerged as one of the main signaling routes utilized by cells to control their increase in size. Here we focus on two components of this pathway, PKB and S6K, and briefly review the experiments that initially uncovered their roles in cell size control. In addition, we discuss a number of recent observations suggesting that (...) the generic models used to describe this pathway to date may have been oversimplified. Indeed, recent observations in Drosophila and mouse support a more complex interaction between these signaling components in development. Finally, we have utilized two contemporary studies involving PKB‐ and S6K‐deficient mice as a paradigm to underscore the importance of cell size and to accurately delineate the connections between signaling pathways for human disease, such as diabetes mellitus. BioEssays 24:65–71, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

Superoxide is produced by a NADPH oxidase of phagocytic cells and contributes to their microbicidal activities. The oxidase is activated when receptors in the neutrophil plasma membrane bind to the target microbe. These receptors recognise antibodies and complement fragments which coat the target cell. The oxidase electron transport chain, located in the plasma membrane, comprises a low potential cytochrome b heterodimer (gp 91‐phox and p22‐phox) associated with FAD. It is non‐functional until at least three proteins, p67‐phox, p47‐phox and p21rac (...) (and possibly others), move from the cytosol to dock on the cytochrome b. The docking involves the interaction of SH3 domains may become exposed follwoing phosphorylation of p47‐phox by protein kinase C or, in model systems, by addition of arachidonic acid to reconstitution mixtures. Following the docking process the electron‐transporting component is able to transfer electrons from NADPH to oxygen. This electrogenic event is charge‐compensated by the opening of a prton channel. Components of the oxidase are expressed in non‐phagocytes, where their function is uncretain but could be related to some signal function of superoxide. (shrink)

Major events of the cell cycle—DNA synthesis, mitosis and cell division—are regulated by a complex network of protein interactions that control the activities of cyclin‐dependent kinases. The network can be modeled by a set of nonlinear differential equations and its behavior predicted by numerical simulation. Computer simulations are necessary for detailed quantitative comparisons between theory and experiment, but they give little insight into the qualitative dynamics of the control system and how molecular interactions determine the fundamental physiological properties (...) of cell replication. To that end, bifurcation diagrams are a useful analytical tool, providing new views of the dynamical organization of the cell cycle, the role of checkpoints in assuring the integrity of the genome, and the abnormal regulation of cell cycle events in mutants. These claims are demonstrated by an analysis of cell cycle regulation in fission yeast. BioEssays 24:1095–1109, 2002. © 2002 Wiley‐Periodicals, Inc. (shrink)

Clinics and hospitals around the globe are offering stem cell treatments to persons with serious conditions for whom no effective therapies are available in their home countries. Many of these treatments, which are touted as cures for such conditions as Parkinson's and Alzheimer's Diseases, multiple sclerosis, and spinal cord injuries, have not gone through clinical trials that establish their safety and efficacy. Indeed, it is unclear whether some of them even utilize stem cells. State regulation of these therapies (...) tends to be weak or nonexistent in some of the countries in which they are offered. This puts those who believe they must travel abroad for stem cell treatments at risk of injury from procedures that .. (shrink)

Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage‐specific and stably expressed transcription factors, combined with input from environmental signals. Lineage‐specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome‐wide and multi‐omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, we discuss (...) functional dynamics of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre‐ and post‐commitment stage‐specific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage‐specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity. (shrink)

Mitochondrial shape change, brought about by molecules that promote either fission or fusion between individual mitochondria, has been documented in several model systems. However, the deeper significance of mitochondrial shape change has only recently begun to emerge: among others, it appears to play a role in the regulation of cell proliferation. Here, I review the emerging interplay between mitochondrial fission‐fusion components with cell cycle regulatory machineries and how that may impact cell differentiation. Regulation of mitochondrial (...) shape may modulate mitochondrial metabolism and/or energetics to promote crosstalk between signaling components and the cell cycle machinery. Focused research in this area will reveal the exact role of mitochondria in development and disease, specifically in stem cell regulation and tumorigenesis. Such research may also reveal whether and how the endosymbiotic event that gave rise to the mitochondrion was crucial for the evolution of cell cycle regulatory mechanisms in eukaryotes that are absent in prokaryotes. (shrink)

Mesenchymal stem cells (MSCs) are present in fat tissues throughout the body, yet little is known regarding their biological role within epidural fat. We hypothesize that debridement of epidural fat and/or subsequent loss of MSCs within this tissue, disrupts homeostasis in the vertebral environment resulting in increased inflammation, fibrosis, and decreased neovascularization leading to poorer functional outcomes post‐injury/operatively. Clinically, epidural fat is commonly considered a space‐filling tissue with limited functionality and therefore typically discarded during surgery. However, the presence of MSCs (...) within epidural fat suggests that itis more biologically active than historically believed and may contribute to the regulation of homeostasis and regeneration in the dural environment. While the current literature supports our hypothesis, it will require additional experimentation to determine if epidural fat is an endogenous driver of repair and regeneration and if so, this tissue should be minimally perturbed from its original location in the spinal canal. Also see the video abstract here https://youtu.be/MIol_IWK1os. (shrink)

Early embryogenesis is marked by a frail Spindle Assembly Checkpoint (SAC). The time of SAC acquisition varies depending on the species, cell size or a yet to be uncovered developmental timer. This means that for a specific number of divisions, biorientation of sister chromatids occurs unsupervised. When error‐prone segregation is an issue, an aneuploidy‐selective apoptosis system can come into play to eliminate chromosomally unbalanced cells resulting in healthy newborns. However, aneuploidy content can be too great to overcome, endangering viability.SAC (...) generates a diffusible signal to lengthen time spent in mitosis if needed, ensuring correct chromosome segregation, a fundamental factor in the generation of euploid cells. Thus, it remains puzzling what benefit could come from delaying SAC acquisition till later in the development. In this review, we describe what is known on SAC acquisition in distinct species and highlight pending research as well as potential applications for such knowledge. (shrink)

Stem cell research regulations are highly variable across nations, notwithstanding shared and common ethical concerns. Dominant in political debates has been the so-called embryo question. However, the permissibility of human embryonic stem cell research varies among national regulatory frameworks. Scholars have explained differences by resorting to notions of political culture, traditions of ethical reasoning, discursive strategies and political manoeuvring of involved actors. Explanations based on the role of religion or other cultural structural variables are also employed. This paper (...) analyses the emerging of the Italian regulatory framework on stem cell research using an analytical framework that considers the interplay between cultural structural features, political culture, traditions of ethical reasoning, institutional settings and the discursive and political agency of the actors involved. It aims also to explain the role of Roman Catholic Church in shaping the Italian stem cell research regulation not by treating religion as an autonomous causal factor, but through the analysis of the agency of Catholic and allied actors in the Italian political culture and institutional setting. (shrink)

Neddylation, a ubiquitylation‐like post‐translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1–4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1‐4 (Cullin‐RING ligases 1–4) and CRL5, respectively. While over‐activation of the neddylation‐CRLs axis occurs frequently in many human cancers, how neddylation‐CRLs regulate the function of (...) immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3‐Cre, and found that while the Ube2f‐Sag E2/E3 pair plays a minimal role, if any, the Ube2m‐Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation. (shrink)

Persons with serious and disabling medical conditions have traveled abroad in search of stem cell treatments in recent years. However, weak or nonexistent oversight systems in some countries provide insufficient patient protections against unproven stem cell treatments, raising concerns about exposure to harm and exploitation. The present article, the first of two, describes and analyzes stem cell tourism in Russia and India and addresses several scientific/medical, ethical, and policy issues raised by the provision of unproven stem (...) class='Hi'>cell-based treatments within them. The distinction between treatment based on proven clinical research and "innovative treatment" is addressed and the authors conclude that the innovations at issue constitute neither. Regulatory measures need to be developed or strengthened in accord with internationally accepted standards in such countries to protect those seeking stem cell treatments. (shrink)