Lycopene treatment inhibits activation of Jak1/Stat3 and Wnt/β-catenin signaling and attenuates hyperproliferation in gastric epithelial cells.
Park Bohye,Lim Joo Weon,Kim Hyeyoung
Nutrition research (New York, N.Y.)
Helicobacter pylori (H pylori) colonizes the human stomach and increases the risk of gastric diseases including gastric cancer. H pylori increases reactive oxygen species (ROS), which activate Janus-activator kinase 1 (Jak1)/signal transducers and activators of transcription 3 (Stat3) in gastric epithelial cells. ROS mediate hyperproliferation, a hallmark of carcinogenesis, by activating Wnt/β-catenin signaling in various cells. Lycopene is a potent antioxidant exhibiting anticancer effects. We hypothesized that lycopene may inhibit H pylori-induced hyperproliferation by suppressing ROS-mediated activation of Jak1/Stat3 and Wnt/β-catenin signaling, and β-catenin target gene expression in gastric epithelial cells. We determined cell viability, ROS levels, and the protein levels of phospho- and total Jak1/Stat3, Wnt/β-catenin signaling molecules, Wnt-1, lipoprotein-related protein 5, and β-catenin target oncogenes (c-Myc and cyclin E) in H pylori-infected gastric epithelial AGS cells. The Jak1/Stat3 inhibitor AG490 served as the control treatment. The significance of the differences among groups was calculated using the 1-way analysis of variance followed by Newman-Keuls post hoc tests. The results show that lycopene reduced ROS levels and inhibited Jak1/Stat3 activation, alteration of Wnt/β-catenin multiprotein complex molecules, expression of c-Myc and cyclin E, and cell proliferation in H pylori-infected AGS cells. AG490 similarly inhibited H pylori-induced cell proliferation, alteration of Wnt/β-catenin multiprotein complex molecules, and oncogene expression. H pylori increased the levels of Wnt-1 and its receptor lipoprotein-related protein 5; this increase was inhibited by either lycopene or AG490 in AGS cells. In conclusion, lycopene inhibits ROS-mediated activation of Jak1/Stat3 and Wnt/β-catenin signaling and, thus, oncogene expression in relation to hyperproliferation in H pylori-infected gastric epithelial cells. Lycopene might be a potential and promising nutrient for preventing H pylori-associated gastric diseases including gastric cancer.
Extracellular signaling molecules to promote fracture healing and bone regeneration.
Hankenson K D,Gagne K,Shaughnessy M
Advanced drug delivery reviews
To date, the delivery of signaling molecules for bone regeneration has focused primarily on factors that directly affect the bone formation pathways (osteoinduction) or that serve to increase the number of bone forming progenitor cells. The first commercialized growth factors approved for bone regeneration, Bone Morphogenetic Protein 2 and 7 (BMP2 and BMP7), are direct inducers of osteoblast differentiation. As well, newer generations of potential therapeutics that target the Wnt signaling pathway are also direct osteoinducers. On the other hand, some signaling molecules may play a role as mitogens and serve to increase the number of bone producing cells or may increase vascularization. This is true for factors such as Platelet Derived Growth Factor (PDGF) or Fibroblast Growth Factor (FGF). Vascular Endothelial Growth Factor (VEGF) likely has a special role. Not only does it induce new blood vessel formation, it also has direct effects on osteoblasts through endothelial cell-based BMP production. In addition to these pathways that classically have targeted bone production, there are also opportunities to target other aspects of the bone healing process such as inflammation, vascularization, and cell ingress to the fracture site. Bone regeneration is highly complex with defined, yet overlapping stages of healing. We will review established and novel extracellular signaling factors associated with various stages of fracture healing that could be targeted to promote enhanced bone regeneration. Importantly, multiple potential cell and tissues could be targeted to enhance healing in addition to focusing solely on osteoinductive therapeutics.
Concurrent inhibition of TGF-β and mitogen driven signaling cascades in Dupuytren's disease - non-surgical treatment strategies from a signaling point of view.
Krause C,Kloen P
Dupuytren's disease (DD) is a benign progressive fibro-proliferative disorder of the fascia palmaris of the hand. Currently, treatment consists of surgical excision with a relatively high recurrence rate and risk of complications. To improve long-term outcome of DD treatment, research focus has shifted towards molecular targets for DD as an alternative to surgery. Therefore, complete and exact understanding of the cause of DD is needed. Transforming growth factor (TGF)-β is considered a key player in DD. We recently showed that increased TGF-β expression in DD correlates not only with elevated expression and activation of downstream Smad effectors, but also with overactive ERK1/2 MAP kinase signaling. Both TGF-β/Smad and non-Smad signaling pathways increase expression of key fibrotic markers and contractility of Dupuytren's myofibroblasts. What is not yet known is whether these two signaling cascades each accelerate DD autonomously, successively or in conjunction. Elucidation of this mechanism will help develop new potential non-surgical treatments. We hypothesize that TGF-β-induced short-term activation of the MAPK pathway leads to an autonomous non-Smad driven fibrosis. Therefore, successful treatment strategies will target not only TGF-β/Smad, but also intracellular MAPK signaling. In this review we discuss possible scenarios in which such a drift from TGF-β induced Smad signaling to autonomous non-Smad signaling could be observed in DD. The potential therapeutic effects of small cytokine signaling cascades inhibitors, such as TGF-β type I receptor-, (pan-) tyrosine- or ERK1/2 MAP-kinase inhibitor will be highlighted. To abrogate the fibrotic trait and the recurrence of DD, we speculate on sequential and co-application of such molecules in order to provide possible new non-operative strategies for DD.
Role of IP₃ receptor in development.
IP₃ receptor is a Ca(2+) release channel localized on the endoplasmic reticulum. IP(3) receptor is composed of three isoforms, which are expressed in various cells and tissues, and play variety of roles throughout development. I here describe the role of IP₃ receptor from oogenesis, meiotic maturation and fertilization. I also describe the Ca(2+) signaling at meiosis and mitosis, and especially the role in early embryogenesis to determine dorso-ventral axis formation. Loss of function mutation of type 1 IP₃ receptor in mouse, both by gene targeting and spontaneous mutations shows severe ataxia and other phenotypes. Interestingly, double knockouts of type 1 and type 2 exhibit cardiogenesis arrest and that of type 2 and type 3 results in exocrine secretion deficit. IP₃R of Drosophila or Caenorhabditis elegans is single gene and mutation results severe phenotype of behavior. All the data described here show that IP₃Rs are essential for life and abnormality of IP(3)Rs results in severe abnormality in its structure and function of organism.
Control of homologous chromosome division in the mammalian oocyte.
Holt Janet E,Jones Keith T
Molecular human reproduction
Homologous chromosomes are segregated during the first meiotic division (meiosis I). Unfortunately, human oocytes are particularly susceptible to mis-segregation errors, so generating aneuploid, often non-viable, embryos. Here we review the cell biology of meiosis I and how homolog disjunction is regulated for mammalian oocytes. We focus on the activity of the anaphase-promoting complex/cyclosome (APC/C), which is responsible for timely degradation of the cohesin component, REC8 and the cyclin B regulatory subunit of maturation-promoting factor, both essential steps for meiosis I completion. In particular, we examine the role played by the spindle assembly checkpoint in controlling the APC/C activity, and in so doing ensuring accurate disjunction of homologs.
Mosaicism in Preimplantation Human Embryos: When Chromosomal Abnormalities Are the Norm.
McCoy Rajiv C
Trends in genetics : TIG
Along with errors in meiosis, mitotic errors during post-zygotic cell division contribute to pervasive aneuploidy in human embryos. Relatively little is known, however, about the genesis of these errors or their fitness consequences. Rapid technological advances are helping to close this gap, revealing diverse molecular mechanisms contributing to mitotic error. These include altered cell cycle checkpoints, aberrations of the centrosome, and failed chromatid cohesion, mirroring findings from cancer biology. Recent studies are challenging the idea that mitotic error is abnormal, emphasizing that the fitness impacts of mosaicism depend on its scope and severity. In light of these findings, technical and philosophical limitations of various screening approaches are discussed, along with avenues for future research.
Mechanisms of kinetochore-microtubule attachment errors in mammalian oocytes.
Kitajima Tomoya S
Development, growth & differentiation
Proper kinetochore-microtubule attachment is essential for correct chromosome segregation. Therefore, cells normally possess multiple mechanisms for the prevention of errors in kinetochore-microtubule attachments and for selective stabilization of correct attachments. However, the oocyte, a cell that produces an egg through meiosis, exhibits a high frequency of errors in kinetochore-microtubule attachments. These attachment errors predispose oocytes to chromosome segregation errors, resulting in aneuploidy in eggs. This review aims to provide possible explanations for the error-prone nature of oocytes by examining key differences among other cell types in the mechanisms for the establishment of kinetochore-microtubule attachments.
Spindle formation, chromosome segregation and the spindle checkpoint in mammalian oocytes and susceptibility to meiotic error.
Vogt E,Kirsch-Volders M,Parry J,Eichenlaub-Ritter U
The spindle assembly checkpoint (SAC) monitors attachment to microtubules and tension on chromosomes in mitosis and meiosis. It represents a surveillance mechanism that halts cells in M-phase in the presence of unattached chromosomes, associated with accumulation of checkpoint components, in particular, Mad2, at the kinetochores. A complex between the anaphase promoting factor/cylosome (APC/C), its accessory protein Cdc20 and proteins of the SAC renders APC/C inactive, usually until all chromosomes are properly assembled at the spindle equator (chromosome congression) and under tension from spindle fibres. Upon release from the SAC the APC/C can target proteins like cyclin B and securin for degradation by the proteasome. Securin degradation causes activation of separase proteolytic enzyme, and in mitosis cleavage of cohesin proteins at the centromeres and arms of sister chromatids. In meiosis I only the cohesin proteins at the sister chromatid arms are cleaved. This requires meiosis specific components and tight regulation by kinase and phosphatase activities. There is no S-phase between meiotic divisions. Second meiosis resembles mitosis. Mammalian oocytes arrest constitutively at metaphase II in presence of aligned chromosomes, which is due to the activity of the cytostatic factor (CSF). The SAC has been identified in spermatogenesis and oogenesis, but gender-differences may contribute to sex-specific differential responses to aneugens. The age-related reduction in expression of components of the SAC in mammalian oocytes may act synergistically with spindle and other cell organelles' dysfunction, and a partial loss of cohesion between sister chromatids to predispose oocytes to errors in chromosome segregation. This might affect dose-response to aneugens. In view of the tendency to have children at advanced maternal ages it appears relevant to pursue studies on consequences of ageing on the susceptibility of human oocytes to the induction of meiotic error by aneugens and establish models to assess risks to human health by environmental exposures.
Spindle assembly and chromosome dynamics during oocyte meiosis.
Mullen Timothy J,Davis-Roca Amanda C,Wignall Sarah M
Current opinion in cell biology
Organisms that reproduce sexually utilize a specialized form of cell division called meiosis to reduce their chromosome number by half to generate haploid gametes. Meiosis in females is especially error-prone, and this vulnerability has a profound impact on human health: it is estimated that 10-25% of human embryos are chromosomally abnormal, and the vast majority of these defects arise from problems with the female reproductive cells (oocytes). Here, we highlight recent studies that explore how these important cells divide. Although we focus on work in the model organism Caenorhabditis elegans, we also discuss complementary studies in other organisms that together provide new insights into this crucial form of cell division.
Hillers Kenneth J,Jantsch Verena,Martinez-Perez Enrique,Yanowitz Judith L
WormBook : the online review of C. elegans biology
Sexual reproduction requires the production of haploid gametes (sperm and egg) with only one copy of each chromosome; fertilization then restores the diploid chromosome content in the next generation. This reduction in genetic content is accomplished during a specialized cell division called meiosis, in which two rounds of chromosome segregation follow a single round of DNA replication. In preparation for the first meiotic division, homologous chromosomes pair and synapse, creating a context that promotes formation of crossover recombination events. These crossovers, in conjunction with sister chromatid cohesion, serve to connect the two homologs and facilitate their segregation to opposite poles during the first meiotic division. During the second meiotic division, which is similar to mitosis, sister chromatids separate; the resultant products are haploid cells that become gametes. In Caenorhabditis elegans (and most other eukaryotes) homologous pairing and recombination are required for proper chromosome inheritance during meiosis; accordingly, the events of meiosis are tightly coordinated to ensure the proper execution of these events. In this chapter, we review the seminal events of meiosis: pairing of homologous chromosomes, the changes in chromosome structure that chromosomes undergo during meiosis, the events of meiotic recombination, the differentiation of homologous chromosome pairs into structures optimized for proper chromosome segregation at Meiosis I, and the ultimate segregation of chromosomes during the meiotic divisions. We also review the regulatory processes that ensure the coordinated execution of these meiotic events during prophase I.
Recombination and chromosome segregation.
Sherratt David J,Søballe Britta,Barre François-Xavier,Filipe Sergio,Lau Ivy,Massey Thomas,Yates James
Philosophical transactions of the Royal Society of London. Series B, Biological sciences
The duplication of DNA and faithful segregation of newly replicated chromosomes at cell division is frequently dependent on recombinational processes. The rebuilding of broken or stalled replication forks is universally dependent on homologous recombination proteins. In bacteria with circular chromosomes, crossing over by homologous recombination can generate dimeric chromosomes, which cannot be segregated to daughter cells unless they are converted to monomers before cell division by the conserved Xer site-specific recombination system. Dimer resolution also requires FtsK, a division septum-located protein, which coordinates chromosome segregation with cell division, and uses the energy of ATP hydrolysis to activate the dimer resolution reaction. FtsK can also translocate DNA, facilitate synapsis of sister chromosomes and minimize entanglement and catenation of newly replicated sister chromosomes. The visualization of the replication/recombination-associated proteins, RecQ and RarA, and specific genes within living Escherichia coli cells, reveals further aspects of the processes that link replication with recombination, chromosome segregation and cell division, and provides new insight into how these may be coordinated.
Chromosome segregation in plant meiosis.
Zamariola Linda,Tiang Choon Lin,De Storme Nico,Pawlowski Wojtek,Geelen Danny
Frontiers in plant science
Faithful chromosome segregation in meiosis is essential for ploidy stability over sexual life cycles. In plants, defective chromosome segregation caused by gene mutations or other factors leads to the formation of unbalanced or unreduced gametes creating aneuploid or polyploid progeny, respectively. Accurate segregation requires the coordinated execution of conserved processes occurring throughout the two meiotic cell divisions. Synapsis and recombination ensure the establishment of chiasmata that hold homologous chromosomes together allowing their correct segregation in the first meiotic division, which is also tightly regulated by cell-cycle dependent release of cohesin and monopolar attachment of sister kinetochores to microtubules. In meiosis II, bi-orientation of sister kinetochores and proper spindle orientation correctly segregate chromosomes in four haploid cells. Checkpoint mechanisms acting at kinetochores control the accuracy of kinetochore-microtubule attachment, thus ensuring the completion of segregation. Here we review the current knowledge on the processes taking place during chromosome segregation in plant meiosis, focusing on the characterization of the molecular factors involved.
Phase separation drives pairing of homologous chromosomes.
Pairing of homologous chromosomes is crucial for ensuring accurate segregation of chromosomes during meiosis. Molecular mechanisms of homologous chromosome pairing in meiosis have been extensively studied in the fission yeast Schizosaccharomyces pombe. In this organism, meiosis-specific noncoding RNA transcribed from specific genes accumulates at the respective gene loci, and chromosome-associated RNA-protein complexes mediate meiotic pairing of homologous loci through phase separation. Pairing of homologous chromosomes also occurs in somatic diploid cells in certain situations. For example, somatic pairing of homologous chromosomes occurs during the early embryogenesis in diptera, and relies on the transcription-associated chromatin architecture. Earlier models also suggest that transcription factories along the chromosome mediate pairing of homologous chromosomes in plants. These studies suggest that RNA bodies formed on chromosomes mediate the pairing of homologous chromosomes. This review summarizes lessons from S. pombe to provide general insights into mechanisms of homologous chromosome pairing mediated by phase separation of chromosome-associated RNA-protein complexes.
Moving and stopping: Regulation of chromosome movement to promote meiotic chromosome pairing and synapsis.
Alleva Benjamin,Smolikove Sarit
Nucleus (Austin, Tex.)
Meiosis is a specialized cellular division occurring in organisms capable of sexual reproduction that leads to the formation of gametes containing half of the original chromosome number. During the earliest stage of meiosis, prophase I, pairing of homologous chromosomes is achieved in preparation for their proper distribution in the coming divisions. An important question is how do homologous chromosomes find each other and establish pairing interactions. Early studies demonstrated that chromosomes are dynamic in nature and move during this early stage of meiosis. More recently, there have been several studies across different models showing the conserved nature and importance of this chromosome movement, as well as the key components involved in chromosome movement. This review will cover these major findings and also introduce unexamined areas of regulation in meiotic prophase I chromosome movement.
Molecular mechanisms of homologous chromosome pairing and segregation in plants.
Zhang Jing,Zhang Bing,Su Handong,Birchler James A,Han Fangpu
Journal of genetics and genomics = Yi chuan xue bao
In most eukaryotic species, three basic steps of pairing, recombination and synapsis occur during prophase of meiosis I. Homologous chromosomal pairing and recombination are essential for accurate segregation of chromosomes. In contrast to the well-studied processes such as recombination and synapsis, many aspects of chromosome pairing are still obscure. Recent progress in several species indicates that the telomere bouquet formation can facilitate homologous chromosome pairing by bringing chromosome ends into close proximity, but the sole presence of telomere clustering is not sufficient for recognizing homologous pairs. On the other hand, accurate segregation of the genetic material from parent to offspring during meiosis is dependent on the segregation of homologs in the reductional meiotic division (MI) with sister kinetochores exhibiting mono-orientation from the same pole, and the segregation of sister chromatids during the equational meiotic division (MII) with kinetochores showing bi-orientation from the two poles. The underlying mechanism of orientation and segregation is still unclear. Here we focus on recent studies in plants and other species that provide insight into how chromosomes find their partners and mechanisms mediating chromosomal segregation.
Centromere pairing precedes meiotic chromosome pairing in plants.
Zhang Jing,Han Fangpu
Science China. Life sciences
Meiosis is a specialized eukaryotic cell division, in which diploid cells undergo a single round of DNA replication and two rounds of nuclear division to produce haploid gametes. In most eukaryotes, the core events of meiotic prophase I are chromosomal pairing, synapsis and recombination. To ensure accurate chromosomal segregation, homologs have to identify and align along each other at the onset of meiosis. Although much progress has been made in elucidating meiotic processes, information on the mechanisms underlying chromosome pairing is limited in contrast to the meiotic recombination and synapsis events. Recent research in many organisms indicated that centromere interactions during early meiotic prophase facilitate homologous chromosome pairing, and functional centromere is a prerequisite for centromere pairing such as in maize. Here, we summarize the recent achievements of chromosome pairing research on plants and other organisms, and outline centromere interactions, nuclear chromosome orientation, and meiotic cohesin, as main determinants of chromosome pairing in early meiotic prophase.
Telomere-mediated chromosome pairing during meiosis in budding yeast.
Rockmill B,Roeder G S
Genes & development
Certain haploid strains of Saccharomyces cerevisiae can undergo meiosis, but meiotic prophase progression and subsequent nuclear division are delayed if these haploids carry an extra chromosome (i. e., are disomic). Observations indicate that interactions between homologous chromosomes cause a delay in meiotic prophase, perhaps to allow time for interhomolog interactions to be completed. Analysis of meiotic mutants demonstrates that the relevant aspect of homolog recognition is independent of meiotic recombination and synaptonemal complex formation. A disome in which the extra chromosome is circular sporulates without a delay, indicating that telomeres are important for homolog recognition. Consistent with this hypothesis, fluorescent in situ hybridization demonstrates that a circular chromosome has a reduced capacity to pair with its homolog, and a telomere-associated meiotic protein (Ndj1) is required to delay sporulation in disomes. A circular dimer containing two copies of the same chromosome delays meiosis to the same extent as two linear homologs, implying that physical proximity bypasses the requirement for telomeres in homolog pairing. Analysis of a disome carrying two linear permuted chromosomes suggests that even nonhomologous chromosome ends can promote homolog pairing to a limited extent. We speculate that telomere-mediated chromosome movement and/or telomere clustering promote homolog pairing.
Time-Course Analysis of Early Meiotic Prophase Events Informs Mechanisms of Homolog Pairing and Synapsis in .
Mlynarczyk-Evans Susanna,Villeneuve Anne M
Segregation of homologous chromosomes during meiosis depends on their ability to reorganize within the nucleus, discriminate among potential partners, and stabilize pairwise associations through assembly of the synaptonemal complex (SC). Here we report a high-resolution time-course analysis of these key early events during meiosis. Labeled nucleotides are incorporated specifically into the chromosomes during the last 2 hr of S phase, a property we exploit to identify a highly synchronous cohort of nuclei. By tracking -labeled nuclei through early meiotic prophase, we define the sequence and duration of chromosome movement, nuclear reorganization, pairing at pairing centers (PCs), and SC assembly. Appearance of ZYG-12 foci (marking attachment of PCs to the nuclear envelope) and onset of active mobilization occur within an hour after S-phase completion. Movement occurs for nearly 2 hr before stable pairing is observed at PCs, and autosome movement continues for ∼4 hr thereafter. Chromosomes are tightly clustered during a 2-3 hr postpairing window, during which the bulk of SC assembly occurs; however, initiation of SC assembly can precede evident chromosome clustering. SC assembly on autosomes begins immediately after PC pairing is detected and is completed within ∼3.5 hr. For the chromosomes, PC pairing is contemporaneous with autosomal pairing, but autosomes complete synapsis earlier (on average) than chromosomes, implying that chromosomes have a delay in onset and/or a slower rate of SC assembly. Additional evidence suggests that transient association among chromosomes sharing the same PC protein may contribute to partner discrimination.