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PubMed1988

Developmental regulation of embryonic genes in plants.

Somatic embryogenesis from cultured carrot cells progresses through successive morphogenetic stages termed globular, heart, and torpedo. To understand the molecular mechanisms underlying plant embryogenesis, we isolated two genes differentially expressed during embryo development. The expression of these two genes is associated with heart-stage embryogenesis. By altering the culture conditions and examining their expressions in a developmental variant cell line, we found that these genes were controlled by the developmental program of embryogenesis and were not directly regulated by 2,4-dichlorophenoxyacetic acid, the growth regulator that promotes unorganized growth of cultured cells and suppresses embryo morphogenesis. These genes are also expressed in carrot zygotic embryos but not in seedlings or mature plants.

Journal Article↗

PubMed1989

Rate, origin, and bidirectionality of Caulobacter chromosome replication as determined by pulsed-field gel electrophoresis.

Cell division in Caulobacter crescentus yields progeny cells that differ with respect to cell structure and developmental program. Chromosome replication initiates in the daughter stalked cell but is repressed in the daughter swarmer cell until later in the cell cycle. To study cell-type-specific DNA initiation, chromosome replication was directly analyzed by pulsed-field gel electrophoresis. Analysis of Dra I restriction fragments of DNA taken at various times from synchronized cell cultures labeled with 2'-deoxy[3H]guanosine has allowed us to determine the origin of DNA replication, the rate and direction of fork movement, and the order of gene replication. The first labeled Dra I fragment to appear contains the site of replication initiation. Based on the correlation of the physical and genetic maps derived by Ely and Gerardot [Ely, B. & Gerardot, C. J. (1988) Gene 68, 323-333], the origin was localized to a 305-kilobase fragment containing the rrnA gene. Furthermore, the sequential replication through unmapped Dra I fragments has enabled us to localize their positions on the genome. The order of appearance of labeled restriction fragments revealed that the chromosome replicates bidirectionally at a fork movement rate of 21 kilobases per minute.

Bacteria↗

PubMed1990

Specific patterns of oncogene activation in transplacentally induced tumors.

Transplacental exposure of rats to a single dose of the direct acting carcinogen methylnitrosourea (MNU) results in the induction of a variety of neoplasias of neuroectodermal, epithelial, and mesenchymal origin. Molecular analysis of the oncogenes present in these tumors revealed a striking degree of tissue specificity. neu oncogenes were found to be reproducibly activated in tumors derived from the peripheral nervous system (PNS), but not in those arising from the central nervous system (CNS). No ras oncogenes were found in either PNS- or CNS-derived tumors. However, Ha-ras oncogenes were detected in each of three mammary carcinomas and Ki-ras oncogenes were present in each of five kidney mesenchymal tumors. These results illustrate that phenotypic expression of activated oncogenes in vivo is not a random process and suggest that normal developmental programs may play an important role in modulating the activation of specific oncogenes by chemical carcinogens. PCR analysis revealed that each of the ras oncogenes detected in these transplacentally induced tumors became activated by the same G----A transition in the second base of codon 12. Since G----A transitions are the preferred mutations induced by MNU, it is likely that these ras oncogenes may have been directly targeted by MNU during embryonic development.

Animals↗

PubMed1993

Target-derived influences on axon growth modes in cultures of trigeminal neurons.

Cellular and molecular signals involved in axon elongation versus collateral and arbor formation may be intrinsic to developing neurons, or they may derive from targets. To identify signals regulating axon growth modes, we have developed a culture system in which trigeminal ganglion cells are challenged by various target tissues. Embryonic day 15 (E15) rat trigeminal ganglion explants were placed between peripheral (vibrissa pad) and central nervous system targets. Normally, bipolar trigeminal ganglion cells extend one process to the vibrissa pad and another to the brainstem trigeminal complex. Under coculture conditions, the peripheral processes invade the vibrissa pad explants and form a characteristic circumfollicular pattern. Central processes of E15 ganglion cells invade many, but not all, central nervous system tissues. In isochronic (E15) central nervous system explants such as brainstem, olfactory bulb, or neocortex, these central processes elongate and form a "tract" but have virtually no arbors. However, in more mature targets (e.g., a section from postnatal brainstem or neocortex), they form arbors instead of a tract. We conclude from these observations that whether trigeminal axons elongate to form a tract, or whether they begin to arborize, is dictated by the target tissue and not by an intrinsic developmental program of the ganglion cell body. The explant coculture system is an excellent model for analysis of the molecular basis of neuron-target interactions.

Animals↗

PubMed1993

Identification in the HLA class I region of a gene expressed late in keratinocyte differentiation.

A gene designated S has been identified in the class I region of the human major histocompatibility complex. The S gene is located 160 kb telomeric of HLA-C. It is expressed at high levels as 2.2-kb and 2.6-kb mRNAs in human skin. No homologous transcripts were detected in other tissues including placenta, liver, spleen, thymus, and brain. In situ hybridization showed that S gene expression was restricted to the differentiating keratinocytes in the granular layer of the epidermis. The predicted amino acid sequence of the S protein was remarkable for its high content of serine, glycine, and proline. There were significant similarities with the amino acid sequences of loricrin, keratin 1, and keratin 10, all major components of the granular-cell layer. The selective expression of the S gene in the granular-cell layer in the epidermis suggests a role in the developmental program of differentiating keratinocytes. Furthermore, in light of the recognized association of psoriasis vulgaris, a disorder of keratinocyte proliferation, with alleles of HLA-C, this gene may contribute primarily to the pathogenesis of this common disorder.

Amino Acid Sequence↗

PubMed1994

Developmentally regulated loss of ubiquitin and ubiquitinated proteins during pollen maturation in maize.

Eukaryotic cells typically contain 0.2-1.0% of their total protein as the highly conserved protein ubiquitin, which exists both free and covalently attached to cellular proteins. The attachment of ubiquitin to cellular proteins occurs posttranslationally by a three-enzyme pathway and results in a peptide linkage of the C terminus of ubiquitin either to a lysyl epsilon-amino group of a substrate protein or to a lysyl epsilon-amino group of a previously linked ubiquitin molecule. The multiple conjugation of ubiquitin to substrate proteins via ubiquitin-ubiquitin linkages is thought to be necessary, but not sufficient, for recognition and degradation by a ubiquitin-dependent protease. In higher plant cells the steady-state level of ubiquitinated proteins is generally constant and can be readily detected in all somatic tissues. In contrast, we have found that a developmentally regulated loss of free ubiquitin and ubiquitinated proteins occurs during maize (Zea mays L.) pollen maturation. This dramatic loss of ubiquitin correlates temporally with commitment to the gametophytic developmental program. Northern blot analysis indicates that the loss of ubiquitin is not due to low levels of ubiquitin mRNA, suggesting that a posttranscriptional regulatory mechanism is responsible.

Blotting, Northern↗

PubMed1996

The control of hematopoiesis and leukemia: from basic biology to the clinic.

Hematopoiesis gives rise to blood cells of different lineages throughout normal life. Abnormalities in this developmental program lead to blood cell diseases including leukemia. The establishment of a cell culture system for the clonal development of hematopoietic cells made it possible to discover proteins that regulate cell viability, multiplication and differentiation of different hematopoietic cell lineages, and the molecular basis of normal and abnormal blood cell development. These regulators include cytokines now called colony-stimulating factors (CSFs) and interleukins (ILs). There is a network of cytokine interactions, which has positive regulators such as CSFs and ILs and negative regulators such as transforming growth factor beta and tumor necrosis factor (TNF). This multigene cytokine network provides flexibility depending on which part of the network is activated and allows amplification of response to a particular stimulus. Malignancy can be suppressed in certain types of leukemic cells by inducing differentiation with cytokines that regulate normal hematopoiesis or with other compounds that use alternative differentiation pathways. This created the basis for the clinical use of differentiation therapy. The suppression of malignancy by inducing differentiation can bypass genetic abnormalities that give rise to malignancy. Different CSFs and ILs suppress programmed cell death (apoptosis) and induce cell multiplication and differentiation, and these processes of development are separately regulated. The same cytokines suppress apoptosis in normal and leukemic cells, including apoptosis induced by irradiation and cytotoxic cancer chemotherapeutic compounds. An excess of cytokines can increase leukemic cell resistance to cytotoxic therapy. The tumor suppressor gene wild-type p53 induces apoptosis that can also be suppressed by cytokines. The oncogene mutant p53 suppresses apoptosis. Hematopoietic cytokines such as granulocyte CSF are now used clinically to correct defects in hematopoiesis, including repair of chemotherapy-associated suppression of normal hematopoiesis in cancer patients, stimulation of normal granulocyte development in patients with infantile congenital agranulocytosis, and increase of hematopoietic precursors for blood cell transplantation. Treatments that decrease the level of apoptosis-suppressing cytokines and downregulate expression of mutant p53 and other apoptosis suppressing genes in cancer cells could improve cytotoxic cancer therapy. The basic studies on hematopoiesis and leukemia have thus provided new approaches to therapy.

Animals↗

PubMed1996

Expression of cyclin D1 in epithelial tissues of transgenic mice results in epidermal hyperproliferation and severe thymic hyperplasia.

To study the involvement of cyclin D1 in epithelial growth and differentiation and its putative role as an oncogene in skin, transgenic mice were developed carrying the human cyclin D1 gene driven by a bovine keratin 5 promoter. As expected, all squamous epithelia including skin, oral mucosa, trachea, vaginal epithelium, and the epithelial compartment of the thymus expressed aberrant levels of cyclin D1. The rate of epidermal proliferation increased dramatically in transgenic mice, which also showed basal cell hyperplasia. However, epidermal differentiation was unaffected, as shown by normal growth arrest of newborn primary keratinocytes in response to high extracellular calcium. Moreover, an unexpected phenotype was observed in the thymus. Transgenic mice developed a severe thymic hyperplasia that caused premature death due to cardio-respiratory failure within 4 months of age. By 14 weeks, the thymi of transgenic mice increased in weight up to 40-fold, representing 10% of total body weight. The hyperplastic thymi had normal histology revealing a well-differentiated cortex and medulla, which supported an apparently normal T-cell developmental program based on the distribution of thymocyte subsets. These results suggest that proliferation and differentiation of epithelial cells are under independent genetic controls in these organs and that cyclin D1 can modulate epithelial proliferation without altering the initiation of differentiation programs. No spontaneous development of epithelial tumors or thymic lymphomas was perceived in transgenic mice during their first 8 months of life, although they continue under observation. This model provides in vivo evidence of the action of cyclin D1 as a pure mediator of proliferation in epithelial cells.

Aging↗

PubMed1996

The hybrid PAX3-FKHR fusion protein of alveolar rhabdomyosarcoma transforms fibroblasts in culture.

Pediatric alveolar rhabdomyosarcoma is characterized by a chromosomal translocation that fuses parts of the PAX3 and FKHR genes. PAX3 codes for a transcriptional regulator that controls developmental programs, and FKHR codes for a forkhead-winged helix protein, also a likely transcription factor. The PAX3-FKHR fusion product retains the DNA binding domains of the PAX3 protein and the putative activator domain of the FKHR protein. The PAX3-FKHR protein has been shown to function as a transcriptional activator. Using the RCAS retroviral vector, we have introduced the PAX3-FKHR gene into chicken embryo fibroblasts. Expression of the PAX3-FKHR protein in these cells leads to transformation: the cells become enlarged, grow tightly packed and in multiple layers, and acquire the ability for anchorage-independent growth. This cellular transformation in vitro will facilitate studies on the mechanism of PAX3-FKHR-induced oncogenesis.

Animals↗

PubMed1996

Integration of circadian and phototransduction pathways in the network controlling CAB gene transcription in Arabidopsis.

The transcription of CAB genes, encoding the chlorophyll a/b-binding proteins, is rapidly induced in dark-grown Arabidopsis seedlings following a light pulse. The transient induction is followed by several cycles of a circadian rhythm. Seedlings transferred to continuous light are known to exhibit a robust circadian rhythm of CAB expression. The precise waveform of CAB expression in light-dark cycles, however, reflects a regulatory network that integrates information from photoreceptors, from the circadian clock and possibly from a developmental program. We have used the luciferase reporter system to investigate CAB expression with high time resolution. We demonstrate that CAB expression in light-grown plants exhibits a transient induction following light onset, similar to the response in dark-grown seedlings. The circadian rhythm modulates the magnitude and the kinetics of the response to light, such that the CAB promoter is not light responsive during the subjective night. A signaling pathway from the circadian oscillator must therefore antagonize the phototransduction pathways controlling the CAB promoter. We have further demonstrated that the phase of maximal CAB expression is delayed in light-dark cycles with long photoperiods, due to the entrainment of the circadian oscillator. Under short photoperiods, this pattern of entrainment ensures that dawn coincides with a phase of high light responsiveness, whereas under long photoperiods, the light response at dawn is reduced.

Arabidopsis↗

PubMed1997

Signaling in plants.

Higher plants are sessile organisms that perceive environmental cues such as light and chemical signals and respond by changing their morphologies. Signaling pathways utilize a complex network of interactions to orchestrate biochemical and physiological responses such as flowering, fruit ripening, germination, photosynthetic regulation, and shoot or root development. In this session, the mechanisms of signaling systems that trigger plant responses to light and to the gaseous hormone, ethylene, were discussed. These signals are first sensed by a receptor and transmitted to the nucleus by a complex network. A signal may be transmitted to the nucleus by any of several systems including GTP binding proteins (G proteins), which change activity upon GTP binding; protein kinase cascades, which sequentially phosphorylate and activate a series of proteins; and membrane ion channels, which change ionic characteristics of the cells. The signal is manifested in the nucleus as a change in the activity of DNA-binding proteins, which are transcription factors that specifically interact and modulate the regulatory regions of genes. Thus, detection of an environmental signal is transmitted through a transduction pathway, and changes in transcription factor activity may coordinate changes in the expression of a portfolio of genes to direct new developmental programs.

Arabidopsis↗

PubMed1995

Occupancy of the Dictyostelium cAMP receptor, cAR1, induces a reduction in affinity which depends upon COOH-terminal serine residues.

Many G-protein-coupled receptors display a rapid decrease in ligand binding following pretreatment with agonist. cAR1, a cAMP receptor expressed early in the developmental program of Dictyostelium, mediates chemotaxis, activation of adenylyl cyclase, and gene expression changes that bring about the aggregation of 10(5) amoebae to form a multicellular structure. Occupancy of cAR1 by cAMP initiates multiple desensitization processes, one of which is an apparent reduction in binding sites. In transformed cells expressing cAR1 constitutively, Scatchard analyses revealed that this apparent loss of ligand binding is largely due to a significant reduction in the affinity of cAR1 for cAMP. A parallel increase in the dose dependence of cAR1-mediated cAMP uptake was observed. Consistent with these findings, proteolysis of intact cells and immunofluorescence suggested that cAR1 remains on the cell-surface following cAMP treatment. Finally, agonist-induced loss of ligand binding is impaired in cAR1 mutants lacking a cluster of cytoplasmic serine residues, which are targets of cAMP-induced phosphorylation.

Amino Acid Sequence↗

PubMed1997

Random mutagenesis of the cAMP chemoattractant receptor, cAR1, of Dictyostelium. Mutant classes that cause discrete shifts in agonist affinity and lock the receptor in a novel activational intermediate.

The cAMP chemoattractant receptor, cAR1, of Dictyostelium transduces extracellular cAMP signals via G protein-dependent and G protein-independent mechanisms. While site-directed mutagenesis studies of G protein-coupled receptors have provided a host of information regarding the domains essential for various functions, many mechanistic and structural questions remain to be resolved. We therefore carried out polymerase chain reaction-mediated random mutagenesis over a large part of the cAR1 sequence (from TMIII through the proximal part of the cytoplasmic tail). We devised a rapid screen for loss-of-function mutations based on the essential role of cAR1 in the developmental program of Dictyostelium. Although there were an average of two amino acid substitutions per receptor, approximately 90% of the mutants were able to substitute for wild-type cAR1 when expressed in receptor null cells. About 2% were loss-of-function mutants that expressed wild-type levels of receptor protein. We used biochemical screens to select about 100 of these mutants and chose eight representative mutants for extensive characterization. These fell into distinct classes. One class had a conditional defect in cAMP binding that was reversed by high salt. Another large class had decreased affinity under all conditions. Curiously, the decreases were clustered into three discrete intervals. One of the most interesting class of mutants lost all capacity for signal transduction but was phosphorylated in response to agonist binding. This latter finding suggests that there are at least two activated states of cAR1 that can be recognized by different downstream effectors.

Animals↗

PubMed1997

Novel repeat elements direct rat proenkephalin transcription during spermatogenesis.

The developmental program controlling sperm formation occurs in multiple stages that sequentially involve mitosis, meiosis, and spermiogenesis. The transcriptional mechanisms regulating these distinct phases are poorly understood. In particular, while a required role for the germ cell transcription factor cyclic AMP response element modulator-tau during spermiogenesis has recently been demonstrated, the transcriptional mechanisms leading to early haploid cell formation are unknown. The rat and mouse proenkephalin genes are selectively expressed from an alternate, germ cell-specific promoter in meiotic and early haploid cells. In this study, the minimal rat proenkephalin germ line promoter was localized to a 116-bp region encompassing the transcriptional start site region. Further, a proximal 51-bp sequence located in the 5'-flanking region is absolutely required for germ line promoter activity. This 51 bp sequence corresponds to a previously characterized binding element (GCP1) that forms cell-specific complexes with rat spermatogenic cell nuclear factors distinct from cyclic AMP response element binding proteins. Further, GCP1 contains novel direct repeat sequences required for factor binding and transgene expression in spermatogenic cells. These repeat elements are highly similar to sequences within the active regions of other male germ line promoters expressed during meiosis. GCP1 may therefore contain transcriptional elements that participate more generally during meiosis in the differentiation of spermatocytes and early haploid spermatids.

Animals↗

PubMed2000

Hypoxia and nitric oxide induce a rapid, reversible cell cycle arrest of the Drosophila syncytial divisions.

Cells can respond to reductions in oxygen (hypoxia) by metabolic adaptations, quiescence or cell death. The nuclear division cycles of syncytial stage Drosophila melanogaster embryos reversibly arrest upon hypoxia. We examined this rapid arrest in real time using a fusion of green fluorescent protein and histone 2A. In addition to an interphase arrest, mitosis was specifically blocked in metaphase, much like a checkpoint arrest. Nitric oxide, recently proposed as a hypoxia signal in Drosophila, induced a reversible arrest of the nuclear divisions comparable with that induced by hypoxia. Syncytial stage embryos die during prolonged hypoxia, whereas post-gastrulation embryos (cellularized) survive. We examined ATP levels and morphology of syncytial and cellularized embryos arrested by hypoxia, nitric oxide, or cyanide. Upon oxygen deprivation, the ATP levels declined only slightly in cellularized embryos and more substantially in syncytial embryos. Reversal of hypoxia restored ATP levels and relieved the cell cycle and developmental arrests. However, morphological abnormalities suggested that syncytial embryos suffered irreversible disruption of developmental programs. Our results suggest that nitric oxide plays a role in the response of the syncytial embryo to hypoxia but that it is not the sole mediator of these responses.

Animals↗

PubMed2001

Friend of GATA 2 physically interacts with chicken ovalbumin upstream promoter-TF2 (COUP-TF2) and COUP-TF3 and represses COUP-TF2-dependent activation of the atrial natriuretic factor promoter.

Friend of GATA (FOG)-2 is a multi-zinc finger transcriptional corepressor protein that binds specifically to GATA4. Gene targeting studies have demonstrated that FOG-2 is required for normal cardiac morphogenesis, including the development of the coronary vasculature, left ventricular compact zone, and heart valves. To better understand the molecular mechanisms by which FOG-2 regulates these cardiac developmental programs, we screened a mouse day 11 embryo library using a yeast two-hybrid interaction trap with the fifth and sixth zinc fingers of FOG-2 as bait. Using this approach, we isolated clones encoding the orphan nuclear receptors chicken ovalbumin upstream promoter-transcription factor (COUP-TF) 2 and COUP-TF3. COUP-TF2-null embryos die during embryonic development with defective angiogenesis and cardiac defects, a pattern that partly resembles the FOG-2-null phenotype. The interaction between COUP-TF2 and FOG-2 in mammalian cells was confirmed by co-immunoprecipitation of these proteins from transfected COS-7 cells. The sites of binding interaction between COUP-TF2 and FOG-2 were mapped to zinc fingers 5 and 6 and fingers 7 and 8 of FOG-2 and to the carboxyl terminus of the COUP-TF proteins. Binding to COUP-TF2 was specific because FOG-2 did not interact with the ligand-binding domains of retinoid X receptor alpha, glucocorticoid receptor, and peroxisome proliferating antigen receptor gamma, which are related to the COUP-TF proteins. Full-length FOG-2 markedly enhanced transcriptional repression by GAL4-COUP-TF2(117-414), but not by a COUP-TF2 repression domain mutant. Moreover, FOG-2 repressed COUP-TF2dependent synergistic activation of the atrial natriuretic factor promoter by both GATA4 and the FOG-2-independent mutant GATA4-E215K. Taken together, these findings suggest that FOG-2 functions as a corepressor for both GATA and COUP-TF proteins.

3T3 Cells↗

PubMed2001

Cloning and biochemical analysis of the tetrahymena origin binding protein TIF1: competitive DNA binding in vitro and in vivo to critical rDNA replication determinants.

Cis-acting type I elements regulate the initiation of DNA replication, replication fork movement, and transcription of the Tetrahymena thermophila rDNA minichromosome and are required for cell cycle-controlled replication and developmentally programmed gene amplification. Previous studies identified three in vitro single-stranded type I element binding activities that were proposed to play distinct roles in replication control. Here we describe the cloning of one of these genes, TIF1, and we provide evidence for its association with type I elements in vivo. Furthermore, we show that TIF1 interacts (in vitro and in vivo) with pause site elements (PSE), which co-localize with replication initiation and fork arrest sites, and are shown to be essential. The in vivo accessibility of PSE and type I elements to potassium permanganate suggests that origin regions are frequently unwound in native chromatin. TIF1 contains sequence similarity to the Solanum tuberosum single strand-specific transcription factor, p24, and a related Arabidopsis protein. Antisense inhibition studies suggest that TIF1 competes with other proteins for PSE and type I element binding. TIF1 displays a marked strand bias in vivo, discriminating between origin- and promoter-proximal type I elements. We propose that this bias selectively modulates the binding of a different subset of proteins to the respective regulatory elements.

Amino Acid Sequence↗

PubMed2006

Bmi-1 regulates the differentiation and clonogenic self-renewal of I-type neuroblastoma cells in a concentration-dependent manner.

Human neuroblastoma I-type cells have been proposed as a population of malignant neural crest stem cells, based on their high tumorigenic potential, expression of stem cell markers, and ability to differentiate into cells of neural crest lineages, including neuroblastic (N-type) and Schwann/glial (S-type) cells. Here, we demonstrate at single cell levels that a subpopulation of I-type cells possess clonogenic self-renewal capacity that requires the Polycomb group family transcription repressor Bmi-1. We further show that Bmi-1 expression levels exert an instructive influence on lineage commitment by I-type cells. Spontaneous and induced differentiation of I-type cells into S-type cells is accompanied by a marked reduction in the level of Bmi-1 expression, and enforced down-regulation of BMI-1 facilitates spontaneous differentiation of I-type cells into S-type cells. By contrast, N-type neuroblastoma cell lines and differentiated N-type cells express higher levels of Bmi-1 relative to I-type cells, and overexpression of BMI-1 promotes the differentiation of I-type cells along the neuronal lineage. Thus, Bmi-1 acts in a concentration-dependent manner in the control of the delicate balance between the self-renewal and differentiation of neuroblastoma I-type cells. These observations suggest that graded activation of a master regulator within individual tumors could trigger divergent developmental programs responsible for both tumor growth and heterogeneity.

Bromodeoxyuridine↗