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PubMed1989

Cancer progression: the ultimate challenge.

I present a new hypothesis for cancer progression, based on observations with experimental tumors and on our growing understanding of the regulation of gene expression in mammalian cells. The experimental observations demonstrate that progression has a stochastic course and is associated with profound perturbations of cell differentiation. The hypothesis proposes that an initial event (such as the activation of an oncogene) alters the state of the regulatory network that controls the expression of cellular genes, directing it to evolve in a direction not consonant with the developmental program of the genome. Possible consequences of this epigenetic hypothesis for cancer research are discussed.

Animals↗

PubMed1983

Synchrony of gene expression and the differentiation of myeloid leukemic cells: reversion from constitutive to inducible protein synthesis.

There are mutant myeloid leukemic cells that cannot be induced to differentiate in serum-free culture medium, or medium with calf serum by the macrophage and granulocyte differentiation-inducing protein (MGI-2) that induces differentiation in normal myeloid cells. These mutants can be induced to differentiate by MGI-2 in medium with mouse serum. The mechanism of this induction of differentiation has been analysed by using two-dimensional gel electrophoresis to study changes in the synthesis of cytoplasmic proteins. In calf serum, 46 of the protein changes that were induced by MGI-2 in normally differentiating cells were constitutive in the differentiation-defective mutant cells. Treatment with mouse serum reverted 13 of these proteins from the constitutive to the non-constitutive state. This reversion was associated with a gain of inducibility for various differentiation-associated properties, so that 23 proteins were induced by MGI-2 for the same type of change as in normal differentiation. A normal developmental program requires synchrony of gene expression. The existence of constitutive instead of inducible gene expression can produce asynchrony in this program and thus produce blocks in differentiation. The results indicate that it is possible to treat these mutant cells so as to induce the reversion of specific proteins from the constitutive to the non-constitutive state, and that this can then restore the synchrony required for induction of differentiation. It is suggested that this mechanism may also allow induction of differentiation in other types of differentiation-defective cells.

Animals↗

PubMed1988

The finger motif defines a multigene family represented in the maternal mRNA of Xenopus laevis oocytes.

We have screened Xenopus laevis cDNA and genomic libraries for finger motif encoding sequences by use of a synthetic oligonucleotide probe coding for a stretch of conserved amino acids, the H/C-link, which joins individual finger loops in several multi-fingered proteins. Our studies reveal that a large number of different cDNA clones encode amino acid sequences predicting multiple units of the metal-coordinating finger structure. Derived proteins are different from each other as well as from the two examples of Xenopus finger proteins reported to date, TFIIIA and X.fin. The 109 finger repeats characterized are derived from 14 different cDNA clones and have been analysed for the presence of conserved and highly variable amino acids, revealing a close structural relatedness among each other as well as with a few selected finger domains from Drosophila and mouse proteins. The results from this comparative sequence analysis are also discussed in terms of the existing models for DNA binding. All sequences are identified in an ovary cDNA library but the patterns of mRNA level for individual finger clones vary greatly during early development. The prevalence of these structures in the oocyte suggests that part of the maternal information for the realization of the developmental program utilized in Xenopus embryogenesis might be transmitted in the form of regulatory, nucleic-acid-binding proteins.

Amino Acid Sequence↗

PubMed1988

Constitutive transcription and regulation of gene expression in non-photosynthetic plastids of higher plants.

The plastid genome in higher plants contains >50 genes for rRNAs, tRNAs and proteins for transcriptional and translational functions, besides the genes encoding photosynthetic proteins. Considering the totipotency of most higher plant cells and the differentiation capacity of plastids, it can be inferred that at least the genes for genetic functions must be constitutively expressed in all plant organs, including non-photosynthetic roots, to maintain a basal level of transcriptional and translational activities. To test this hypothesis, transcription, RNA accumulation and polysome formation were analyzed in root amyloplasts, and in plastids from hypocotyls and cotyledons of dark-grown spinach seedlings. The results for 10 representative genes show that they are constitutively transcribed at relative rates which are similar in root amyloplasts and leaf chloroplasts. The differential accumulation of their mRNAs in roots and other non-photosynthetic plant organs is controlled at the post-transcriptional level by a developmental program. Although mRNAs for photosynthetic proteins are detectable in root amyloplasts, some of them are specifically depleted from polysomes relative to mRNAs for ribosomal proteins. This translational discrimination does not result from modifications in splicing or 5'- and 3' -end processing of mRNAs for photosynthetic proteins, since processing is identical in root amyloplasts and leaf chloroplasts. The results support the model of constitutive transcription of the plastid genome, and indicate that the expression of most plastid genes in spinach plants is controlled primarily by post-transcriptional and translational mechanisms.

Journal Article↗

PubMed1990

Constitutive overexpression of the contact site A glycoprotein enables growth-phase cells of Dictyostelium discoideum to aggregate.

The contact site A (csA) glycoprotein is a developmentally regulated cell adhesion molecule which mediates EDTA-stable cell contacts during the aggregation stage of Dictyostelium discoideum. A transformation vector was constructed which allows overexpression of the csA protein during the growth phase. In that stage the csA protein is normally not expressed; in the transformants it was transported to the cell surface and carried all modifications investigated, including a phospholipid anchor and two types of oligosaccharide chain. csA expression enabled the normal non-aggregative growth-phase cells to form EDTA-stable contacts in suspension and to assemble into three-dimensional aggregates when moving on a substratum. After prolonged cultivation of csA overexpressing transformants in nutrient medium the developmental program was found to be turned on, as it normally occurs only in starving cells. During later development of transformed cells, the csA glycoprotein remained present on the cell surface, while it is down-regulated in the wild type. It was detected in both the prestalk and prespore regions of the multicellular slugs made from transformed cells.

Antibodies, Monoclonal↗

PubMed1991

Epithelio--mesenchymal interactions are critical for Quox 7 expression and membrane bone differentiation in the neural crest derived mandibular mesenchyme.

In higher vertebrates, branchial arch mesenchyme (ectomesenchyme) is derived from the cephalic neural crest. The ectomesenchyme of the mandibular arch yields the Meckel's cartilage and several membrane bones. We previously reported the isolation of a quail homeobox gene, Quox 7. In common with its mouse counterpart Hox 7, Quox 7 is highly expressed in the medioventral part of the mandibular arch and later in the precursor cells of the membrane bones. Since bone differentiation from ectomesenchyme is strictly dependent upon a signal provided by the mandibular epithelium, we decided to see whether the regulation of Quox 7 gene activity might be correlated with epithelio--mesenchymal interactions. Quox 7 expression was studied in E3 mandibular ectomesenchyme cultured in vitro or grafted on the chick chorioallantoic membrane either alone or recombined with the homotopic and heterotopic epithelia. We found that Quox 7 mRNA was undetectable after 48 h in cultures of mesenchyme alone while it remained abundant in non-cartilaginous tissue of the mandibular arch ectomesenchyme recombined with its own epithelium. The signal provided by the mandibular epithelium for Quox 7 expression can also arise from various heterotopic epithelia, e.g. of dorsal or ventral body wall and of limb bud. Thus the effect of the epithelium on Quox 7 expression in mesenchymal cells strictly parallels that on bone formation. These results strongly suggest that the epithelio-mesenchymal interactions have an essential role on the regulation of Quox 7 gene, the product of which seems to be, in turn, necessary for the execution of the skeletal developmental program in the facial area.

Animals↗

PubMed2001

Genetic lesions and perturbation of chromatin architecture: a road to cell transformation.

Differential gene expression is a rigorously precise procedure that defines the developmental program of cells, tissues, organs, and of the entire organism. The correct execution of this program requires the participation of multiple and complex groups of regulators. In addition to transcription factors, which are key tools in ontogenesis by providing sequential switch of different genes, the structure of the chromatin is a dominant determinant leading to gene expression. Through the novel and insightful work of several investigators, it appears that the architecture of the chromatin spanning the genes can and does influence the efficiency of RNA transcription, and therefore of gene expression. Several new enzymatic complexes have been identified that reversibly modify the chromatin architecture by methylation, phosphorylation, and acetylation of the nucleosomal core proteins. These enzymes are crucial for the proper balance and maintenance of gene expression, and are often the target of mutations and alterations in human cancer. Here, we review briefly the current models proposing how some of these enzymes normally modify the chromatin structure and how their functional disruption leads to inappropriate gene expression and cell transformation.

Acetylation↗

PubMed1985

Regulation of discoidin I gene expression in dictyostelium discoideum by cell-cell contact and cAMP.

We have previously presented evidence that cell-cell contact is the normal developmental signal to deactivate discoidin I gene expression in D discoideum [Berger EA, Clark JM: Proc Natl Acad Sci USA 80:4983, 1983]. Here we provide genetic evidence to support this hypothesis by examining gene expression in a cohesion-defective mutant, strain EB-21, which enters the developmental program but is blocked at the loose mound stage. When this strain was developed in suspension, the cells remained almost entirely as single amoebae, unlike the wild type, which formed large multicellular aggregates. In both strains, discoidin I mRNA levels were low in vegetative cells but rose sharply during the first few hours of development. However, the peak level reached at 8 hr in EB-21 exceeded that observed in wild type, and while the level declined markedly over the next few hours in wild type, it remained highly elevated in the mutant. Thus, there was a correlation between the inability of EB-21 to form normal cell-cell contacts and its deficiency in inactivating discoidin I gene expression. Previous studies from several laboratories, including this one, have demonstrated that exogenously added cAMP can block or reverse the changes in gene expression normally seen upon cell disaggregation. This has led us to propose that cAMP serves as a second messenger regulating the expression of contact-regulated genes. Here we provide additional support for this hypothesis. Intracellular cAMP levels rapidly dropped several-fold when wild type tight cell aggregates were disaggregated and remained low as the cells were cultured in the disaggregated state. Furthermore, overexpression of discoidin I mRNA late in development in EB-21 was corrected by addition of high concentrations of cAMP. These results are consistent with a second messenger function for cAMP in the contact-mediated regulatory response, and they indicate that the cAMP response machinery for discoidin I gene expression is capable of functioning in the cohesion-defective EB-21 strain.

Cyclic AMP↗

PubMed1975

The molecular genetics of mammalian glucuronidase.

The genetic factors known to be involved in the final realization of beta-glucuronidase activity in mice are considered from the standpoint of structural genes determining the catalytic activity of enzyme molecules as well as the recognition features of enzyme molecules that identify them for subsequent processing by the cell; processing genes determining the cellular apparatus involved with the conjugation, intracellular localization and eventual degradation of enzyme molecules; regulatory genes determining rates of enzyme synthesis, especially in response to physiological signals such as hormones; and temporal genes determining the developmental programs for expression of these classes during growth and differentiation. The properties of genetic variants of beta-glucuronidase falling into each of these classes are described. When those results are considered in concert with the properties of genetic variants known for other mammalian enzymes several generalizations emerge. Structural genes of enzymes are not usually linked to the processing genes determining the post-assembly events in the life of that enzyme. In contrast, all of the regulatory and temporal gene sites so far identified are in close proximity to the structural genes they modulate. Regulatory and temporal sites appear to act in a cis fashion to control the amount of enzyme synthesized from the adjacent structural allele on the same chromosome.

Animals↗

PubMed1977

Cytodifferentiation in the accessory glands of Tenebrio molitor II. Patterns of leucine incorporation in the tubular glands of post-ecdysial adult males.

The tubular accessory gland of male mealworm beetles undergoes rapid and progressive terminal differentiation in the 8-day period after ecdysis to the adult. Total protein and RNA content are maximal at five and eight days respectively. Rates of leucine incorporation rise gradually through the first four days and then increase abruptly in the 5-to 7-day interval. SDS-polyacrylamide gel electrophoresis demonstrates a variety of proteins; two classes with high mobility (Class A and B) appear prominent in homogenates of 5- to 8-day glands. Double-label procedures show that as the glands mature, an increasing proportion of the total leucine incorporation passes into Class A and B proteins, until at eight days, Class A and B proteins account for 50% of the total for the gland. The relative incorporation into A vs. B also changes linearly over this interval. The developmental program of the tubular gland includes both a linearly biosynthetic increase in the proportion of differentiation-specific proteins and an abrupt change in the overall rates of leucine incorporation.

Age Factors↗

PubMed1979

Germinal vesicle configurations and patterns of polypeptide synthesis of procine oocytes from antral follicles of different size, as related to their competency for spontaneous maturation.

The cytogenetic configurations of germinal vesicle (gv) chromatin were analyzed for pools of porcine oocytes harvested from small (1.0-2.0 mm), medium (3.0-5.0 mm), and large (6.0-10.0 mm) antral follicles. Groups of oocytes from these follicular classes also were examined by high-resolution, two-dimensional, polyacrylamide gel electrophoresis to compare their patterns of polypeptide synthesis. The results show a high incidence of gross and cytogenetic degeneration among oocytes from small antral follicles as compared with those from medium or lage follicles. Pools of oocytes could be separated, on the basis of gross morphology and integrity of adherent granulosa cells, into two classes: "Type A" which appeared normal, and "type B" which appeared to be atretic. Among selected "type A" oocytes a particular chromatin configuration, termed "fibrous" characterizes the gv of oocytes from small follicles; whereas a different configuration, termed "diffuse," characterizes the gv of oocytes from large follicles. The patterns of polypeptide synthesis were markedly different for samples of "type A" oocytes of the three follicular classes; and the patterns for oocytes from medium and large follicles were more similar to each other than to patterns for oocytes from slall follicles. The incidences of maturational development beyond the gv stage in vitro were similar for "type A" oocytes from the three follicular classes (i.e., 66% to 82% maturation); although "type B" oocytes underwent maturation beyond the gv at a significantly reduced incidence (i.e., 20% to 29% maturation). "Type A" oocytes from large follicles completed maturation in vitro (i.e., underwent the first meiotic division) at a significantly higher incidence (55%) than did oocytes from small (11% to 20%) or medium (16%) follicles. Our findings are consistent with the hypotheses that a high proportion of oocytes from small antral follicles are atretic, and that a developmental program controls the molecular and cytogenetic changes occurring in porcine oocytes during follicular growth. These changes appear to be highly correlated with the acquisition of competency to complete maturation in vitro, and possibly also are required for normal fertilization and embryogenesis.

Animals↗

PubMed1987

Innervation is necessary for the development of fast contraction kinetics of singing muscles in a katydid.

The twitch duration of mesothoracic wing muscles of the male katydid Neoconocephalus robustus (Insecta; Orthoptera; Tettigoniidae) decreases rapidly within the first 5 days of adulthood, to about half of its value in newly molted adults. To determine if this change is dependent upon neural input, male mesothoracic first tergocoxal muscles were unilaterally denervated on the second day of adulthood. The contraction kinetics of the denervated and contralateral innervated muscles were tested four days later. The development of rapid contraction kinetics was slowed or stopped in the denervated muscles, while the contralateral innervated muscles did become faster. Mesothoracic wing muscles of females do not develop faster contraction kinetics. When the female mesothoracic first tergocoxal muscle is denervated, there is no difference in twitch duration after 4 days between the innervated and contralateral denervated muscles. Therefore, denervation in newly molted adult male katydids interrupts a developmental program for the acquisition of adult contraction kinetics.

Animals↗

PubMed1988

Stability of the glandular morphogenesis produced by retinoids in the newborn hamster cheek pouch in vitro.

Retinoids can induce alterations in differentiation and morphogenesis in the hamster cheek pouch. In order to determine the stability of these changes, explants of neonatal pouch were exposed to 6 micrograms/ml of either retinyl acetate (RAc: 1.8 x 10(-5) M) or all-trans retinoic acid (RA: 2.0 x 10(-5) M) for an initial 3 of 7 days, out of a total of 21 days in organ culture. Three days of RAc or RA caused a delay in the differentiation and keratinization of the epithelium at least up to day 7 of culture. Additionally, two out of ten explants exposed to RA showed small downgrowths of epithelium into the stroma at 7 or 14 days. Seven days of exposure to either retinoid led to inhibition of epithelial keratinization, and produced a mucous metaplasia which was still seen at the end of the 21-day culture period. Periodic acid-Schiff (PAS)-positive, diastase-resistant material was present in the metaplastic epithelium, in intercellular, and in some instances, intracellular locations. An excess of either RAc or RA, for 7 days, induced persistent glandlike downgrowths of epithelium, suggesting that a stable alteration in the developmental program of the epithelium may have occurred. Many of these downgrowths possessed a lumen which was lined by cuboidal epithelium and contained PAS-positive, diastase-resistant secretory material. RA appeared more potent than RAc in inhibiting keratinization, in producing a mucous metaplasia, and in initiating glandlike downgrowths. The persistence of glandular downgrowths suggests that retinoids, either directly or indirectly, act in a manner similar to that of an embryonic inductor.

Animals↗

PubMed1991

Fibroblast growth factor and culture in monolayer rescue mesoderm cells destined to die in the developing avian wing.

In an effort to elucidate control mechanisms for developmentally programmed cell death, conditions were sought that rescue the cells destined to die. Three areas of mesodermal cell death in the chick wing were examined: the posterior necrotic zone (PNZ), the opaque patch (OP), and apical mesoderm. The PNZ and OP are areas of normally programmed cell death, whereas the apical mesoderm undergoes cell death only after the overlying apical ectodermal ridge is excised. Cell death in vitro was quantitated using the chromium-release assay. While these tissues undergo apparently normal cell death in organ culture, in monolayer culture almost all are rescued. In addition, the cells are rescued by the addition of fibroblast growth factor to organ cultures. Since fibroblast growth factor is present in decreasing amounts in the limb at this stage of development, normal cell death may occur upon withdrawal of growth factor.

Animals↗

PubMed2006

Caudal autotomy and regeneration in lizards.

Caudal autotomy, or the voluntary self-amputation of the tail, is an anti-predation strategy in lizards that depends on a complex array of environmental, individual, and species-specific characteristics. These factors affect both when and how often caudal autotomy is employed, as well as its overall rate of success. The potential costs of autotomy must be weighed against the benefits of this strategy. Many species have evolved specialized behavioral and physiological adaptations to minimize or compensate for any negative consequences. One of the most important steps following a successful autotomous escape involves regeneration of the lost limb. In some species, regeneration occurs rapidly; such swift regeneration illustrates the importance of an intact, functional tail in everyday experience. In lizards and other vertebrates, regeneration is a highly ordered process utilizing initial developmental programs as well as regeneration-specific mechanisms to produce the correct types and pattern of cells required to sufficiently restore the structure and function of the sacrificed tail. In this review, we discuss the behavioral and physiological features of self-amputation, with particular reference to the costs and benefits of autotomy and the basic mechanisms of regeneration. In the process, we identify how these behaviors could be used to explore the neural regulation of complex behavioral responses within a functional context.

Animals↗

PubMed2003

Developmental basis of evolutionary digit loss in the Australian lizard Hemiergis.

Loss of limb skeletal elements is a recurring theme in tetrapod evolution, but the developmental mechanisms underlying this phenomenon remain largely unknown. The Australian lizard genus Hemiergis offers an excellent model system to study limb reduction among closely related, naturally occurring populations with different numbers of digits. Evolutionary digit loss in Hemiergis does not result from simple truncation of a pentadactyl skeletal developmental program. Rather, the duration of embryonic expression of the patterning molecule Sonic hedgehog (SHH) is shortened in limbs with reduced numbers of digits, and is correlated with decreased cell proliferation in the posterior aspect of the limb. Moreover, this comparative analysis suggests an early role for SHH in specification of digit identity and later importance in maintaining cell proliferation and survival. Subtle changes in spatial or temporal regulation of SHH may alter proliferation and patterning of the developing limb, thereby effecting divergence in adult limb morphology among closely related species. In contrast, expression of MSX and Distal-less proteins were similar among embryos from different populations.

Animals↗

PubMed2003

ARNT gene multiplicity in amphibians: characterization of ARNT2 from the frog Xenopus laevis.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is a member of the Per-ARNT-Sim (PAS) protein superfamily, transcription factors that mediate the cellular responses to various developmental signals and environmental conditions. A beta-class ("partner") PAS protein, ARNT exhibits the capacity to form transcriptionally active heterodimers with several alpha-class ("sensor") proteins, including the aryl hydrocarbon receptors (AHRs), the hypoxia-inducible factors (HIFs), and the Single minded (Sim) proteins. Two genes encode different forms of ARNT in mammals: ARNT1, which is widely expressed, and ARNT2, which is limited to the brain and kidneys of adults and specific neural and branchial tissues of embryos. In contrast, fish apparently express only a single ARNT gene, although in different species, this may be either ARNT1 or ARNT2. In efforts to understand the evolution of ARNT proteins throughout the vertebrate lineage, we isolated an ARNT cDNA from early life stages of the amphibian Xenopus laevis. The encoded protein binds cognate DNA sequences in concert with mouse AHR. Phylogenetic analysis reveals that this sequence is orthologous to mammalian ARNT2 and paralogous to the recently reported X. laevis ARNT1. ARNT2 mRNA expression begins later than ARNT1 (stage 22 vs. stage 8), suggesting the two proteins play distinct roles during development. Hence, in the expression of two well-conserved ARNT paralogs with distinct expression patterns, X. laevis resembles mammals rather than fish. Diversity in the number and function of PAS proteins, including ARNT, may underlie significant species differences in developmental programming and biochemical response to environmental conditions. The identification of multiple amphibian ARNT paralogs represents an important step in the understanding of evolution and functional variation of ARNT in vertebrates.

Amino Acid Sequence↗

PubMed2005

Monitoring synaptogenesis in the developing mouse cerebellum with an original oligonucleotide microarray.

Use of DNA microarrays in neuroscience have been limited to rough screening purposes, mainly because the reliability and sensitivity of available arrays are not high enough. Because only a few hundred to one thousand genes are usually found to change expression levels in most experiments, we attempted to develop a more quantitative array by the following strategies: 1) limit the genes to those relevant to the experimental system, 2) design oligonucleotide probes of specified molecular properties so that more stringent hybridization conditions can be employed, 3) place six spots per probe on one slide and use multiple normalization genes, and 4) use a new type of gold-coated slide with higher S/N ratio. Genes involved in the construction and functioning of the synapse were selected from the literature as well as experimentally by comparing cerebella from hypothyroid and control mice at postnatal day 15 (P15). Although the number of genes covered was not yet large (172 genes), the custom array "Synaptoarray" thus constructed was capable of detecting +/-20% difference in gene expression ratios. Analysis of the postnatal development of the mouse cerebellum by using Synaptoarray demonstrated a general expression pattern with a peak at P7, followed by a decline at P15 and a partial recovery after P21. P10 clearly marked the end of the initial growth stage and a major transcriptional turning point in this system. This result suggests that such a custom array should be useful in monitoring perturbations to the normal developmental program.

Animals↗