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PubMed2000

Development and assessment of a general theory of cervical carcinogenesis utilizing a severe combined immunodeficiency murine-human xenograft model.

OBJECTIVE: Currently, we lack a theoretical explanation for why squamous cell cervical cancer develops predominantly in specific sites (i.e., along the squamocolumnar junction). We therefore implanted human cervical tissues containing the transformation zone in severe combined immunodeficiency (SCID) mice and studied morphology, steroid effects, gene expression, and human papillomavirus (HPV) factors. METHODS: Normal and dysplastic human cervical tissues (3 x 2 mm) were placed subcutaneously in SCID-beige mice and later assessed by in situ hybridization for HPV 16/18 DNA and by immunohistochemistry for expression of CD31, keratin, proliferating-cell nuclear antigen, HPV 16 E6, p53, and Notch-1 (a binary cell fate determination protein). Some normal tissues were implanted with either a 90-day release 1.7-mg 17beta-estradiol pellet or a 5-mg tamoxifen pellet; others were infected prior to implantation with human recombinant adenovirus 5 vector containing a human cytomegalovirus promoter-driven beta-galactosidase gene and later assessed by X-gal staining. RESULTS: Murine and human vessels formed anastomoses by 3 weeks. For at least 11 weeks, normal tissue retained the transformation zone and normal cell-type-specific keratin expression and exhibited normal proliferation; Notch-1 was present only in the basal cell layer. Dysplastic tissues exhibited koilocytosis, increased levels of cellular proliferation, and aberrant keratin, p53, and Notch-1 expression; HPV 16/18 DNA and HPV 16 E6 protein were detected for at least 6 weeks. Squamous metaplasia of normal cervical epithelium resulted from estrogen exposure, and a predominant columnar differentiation pattern was associated with tamoxifen administration. Through stable adenovirus infection, beta-galactosidase was expressed for at least 6 weeks. CONCLUSIONS: This small manipulatable xenograft model maintains normal and dysplastic human cervical epithelium through neovascularization. Neoplastic tissue retains HPV 16/18 DNA and a premalignant phenotype, including elevated levels of cellular proliferation and aberrant keratin, p53, and Notch-1 expression. These attributes constitute essential features of a biologic model through which one may study HPV-mediated human disease and may be superior to cell culture and transgenic murine systems. Furthermore, this may serve as a model for gene therapy. Finally, we suggest that the normal cervical epithelium is maintained through putative interactions between the Notch locus and cell cycle growth regulators such as p53 and pRb. Neoplastic cervical epithelium may arise through disruption of this pathway. This theory may be testable in our animal model.

Animals↗
PubMed2004

Teething with IKKalpha to make notches.

Sharpe and colleagues unveil a crucial role for NF-kappaB activity in tooth development, and show that IKKalpha functions both within and independently from the NF-kappaB pathway during molar and incisor morphogenesis, respectively (in the February issue of Developmental Cell).

Animals↗
PubMed2002

Developmentally-related candidate retinoic acid target genes regulated early during neuronal differentiation of human embryonal carcinoma.

Embryonal carcinoma is a model of embryonic development as well as tumor cell differentiation. In response to all-trans retinoic acid (RA), the human embryonal carcinoma (EC) cell line, NT2/D1, differentiates toward a neuronal lineage with associated loss of cell growth and tumorigenicity. Through the use of cDNA-based microarrays we sought to identify the early downstream targets of RA during differentiation commitment of NT2/D1 cells. A total of 57 genes were induced and 37 genes repressed by RA. RA regulated genes were restricted at 8 h with 27 genes induced and five repressed. The total number of RA-responsive transcripts increased at 24 and 48 h and their pattern of expression was more symmetrical. For a given time point less than 1% of the 9128 cDNAs on the expression array were regulated by RA. Many of these gene products are associated with developmental pathways including those of TGF-beta (Lefty A, NMA, follistatin), homeo domain (HoxD1, Meis2, Meis1, Gbx2), IGF (IGFBP3, IGFBP6, CTGF), Notch (manic fringe, ADAM11), Hedgehog (patched) and Wnt (Frat2, secreted frizzled-related protein 1) signaling. In addition a large cassette of genes induced by RA at 24-48 h are associated with cell adhesion, cytoskeletal and matrix remodeling, growth suppression and intracellular signaling cascades. The majority of repressed genes are associated with protein/RNA processing, turnover or metabolism. The early induced genes identified may play a regulatory role in RA-mediated growth suppression and terminal differentiation and may have physiologic or pharmacologic importance during normal human development and retinoid-based cancer therapy or prevention.

Carcinoma, Embryonal↗
PubMed2004

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas.

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Annexin A5↗
PubMed1975

Axon voltage-clamp simulations. A multicellular preparation.

In this paper we extend the simulation of the voltage clamp of a single nerve fiber to a bundle of axons. These simulations included not only the description of the voltage clamp circuit and a single unidimensional cable to represent the preparation in the "node" region of a double sucrose gap used previously but also a series resistance and a shunt pathway. The output of the voltage control amplifier is applied across the membrane plus the series resistance, producing a voltage drop across the series resistance due to the current generated by the membrane in response to a depolarizing voltage step. Since the membrane current has an inward and an outward phase, voltage drops of opposite sign are produced across the series resistance. During the transient current and at all points along an axon, the potential deviation produced by the series resistance is opposite to the deviation produced by the longitudinal gradient. Only at a command potential equal to the sodium equilibrium potential, the membrane potential transiently matches the command potential. For the attempted voltage clamp of an axon, values of series resistance larger than 50 omega-cm2 allowed propagated action potentials in the membrane. In spite of the presence of propagated action potentials at the calbe membrane, the recorded current does not show "notches" and it has a phase of inward current and a phase of outward current. It is concluded that, in a multicellular preparation with series resistance, the recording of a square voltage pulse does not indicate voltage control of the transmembrane potential. The presence of a shunt pathway produces inaccurate values of current density. Neither series or shunt resistance produce "notches" in the current records.

Action Potentials↗
PubMed1996

[Analysis of changes in repolarization for the differential diagnosis of narrow QRS supraventricular tachycardia and the site of the accessory pathway].

In view of the growing role of catheter ablation techniques for the treatment of supraventricular tachycardia, noninvasive determination of tachycardia mechanism and preliminary localization of the accessory pathway (AP) can simplify the cardiac catheterization procedure and reduce fluoroscopic exposure. The purpose of this study was to analyze the diagnostic value of repolarization changes during narrow QRS complex tachycardia (< 0.11 s). In 159 12-lead electrocardiograms during narrow QRS complex tachycardia (13 atrial tachycardias, 57 atrioventricular (AV) node reentrant tachycardias and 89 AV reciprocating tachycardias), the following were evaluated: 1) the tachycardia cycle length; 2) the presence of QRS alternans > or = 1 mm in at least 6 leads; 3) the presence of ST segment depression > or = 2 mm and/or T wave changes (inversion, notching); 4) the duration of retrograde atrial activation during tachycardia (right atrium-coronary sinus interval, in ms); the latter parameter, as well as tachycardia mechanism and accessory pathway location, were determined during an electrophysiologic study. There were no significant differences in mean cycle length among the groups. ST segment depression > or = 2 mm and/or T wave changes were present more often in AV reciprocating tachycardias (51/89) than in the other groups (AV node reentrant tachycardias: 14/57; atrial tachycardias: 1/13; p < 0.001), independently from the cycle length. Distinct patterns of repolarization changes during tachycardia were associated with different location of accessory pathway: ST segment depression from V3 to V6 in left lateral AP; T wave inversion in inferior leads in posterior-posteroseptal AP; T wave changes in V2 in all cases of anteroseptal AP location. The magnitude of ST segment depression, significantly more marked in the AV reciprocating tachycardias (1.3 +/- 1.6 mm) than in AV node reentrant tachycardias (0.7 +/- 0.8 mm, p < 0.005), was directly related to the duration of atrial activation time during tachycardia (80 +/- 20 ms, and 32 +/- 12 ms, p < 0.001, respectively). The finding of ST segment depression and/or T wave changes during narrow QRS tachycardia suggest the presence of an AV reciprocating tachycardia; this phenomenon may be related to a different pattern of retrograde atrial activation. In conclusion, analysis of repolarization changes during narrow QRS tachycardia constitutes an additional electrocardiographic criterion to differentiate the tachycardia mechanism and, furthermore, can guide preliminary location of the AP, even in the absence of ventricular preexcitation.

Adolescent↗
PubMed2004

The Drosophila F box protein archipelago regulates dMyc protein levels in vivo.

BACKGROUND: The Myc oncoprotein is an important regulator of cellular growth in metazoan organisms. Its levels and activity are tightly controlled in vivo by a variety of mechanisms. In normal cells, Myc protein is rapidly degraded, but the mechanism of its degradation is not well understood. RESULTS: Here we present genetic and biochemical evidence that Archipelago (Ago), the F box component of an SCF-ubiquitin ligase and the Drosophila ortholog of a human tumor suppressor, negatively regulates the levels and activity of Drosophila Myc (dMyc) protein in vivo. Mutations in archipelago (ago) result in strongly elevated dMyc protein levels and increased tissue growth. Genetic interactions indicate that ago antagonizes dMyc function during development. Archipelago binds dMyc and regulates its stability, and the ability of Ago to bind dMyc in vitro correlates with its ability to inhibit dMyc accumulation in vivo. CONCLUSIONS: Our data indicate that archipelago is an important inhibitor of dMyc in developing tissues. Because archipelago can also regulate Cyclin E levels and Notch activity, these results indicate how a single F box protein can be responsible for the degradation of key components of multiple pathways that control growth and cell cycle progression.

Amino Acid Sequence↗
PubMed1997

Gene regulation in the formation of the central nervous system.

In this review recent advances in our understanding of the genetic control of central nervous system development will be discussed. Stem and/or progenitor cells in the neuroepithelium of the neural tube differentiate into neurons and glial cells in the brain and spinal cord. There is an emerging picture of how key regulatory genes act to control various steps in this differentiation pathway, including organization along the anterio-posterior and dorso-ventral body axes. Examples from our own research on nestin and Notch genes will also be presented. It is our hope that information about the biology of these genes may shed light on the nature of the central nervous system stem cell and its developmental decisions.

Animals↗
PubMed2000

Murine Delta homologue, mDelta1, expressed on feeder cells controls cellular differentiation.

The Delta/Serrate-Notch pathway is involved in intercellular signaling that controls cell fate during the development of invertebrates and vertebrates. Delta is a prototype of Notch ligands and has been studied extensively in Drosophila. In higher vertebrates, four Delta/Serrate homologues and four Notch homologues have been identified. Recent studies showed that the murine Delta homologue, mDelta1, is essential in early embryogenesis. The biological activity of mammalian Delta and its roles in cellular differentiation, however, have remained unclear. In this study, we first surveyed expression of mDelta1 in the adult mouse and found it to be present in a wide range of tissues. For testing biological activity of mDelta1, we expressed a mDelta1 full-length cDNA in L cells using a eukaryotic expression vector. Effects of mDelta1 on cellular differentiation were examined in two independent systems, featuring C2C12 myogenic differentiation and multipotent murine bone marrow cell differentiation. Inhibition of the former was observed with mDelta1 expression on L cells, associated with suppression of myogenin, a myogenic transcription factor. Expression of mDelta1 in conjunction with GM-CSF promoted differentiation of bone marrow cells to myeloid dendritic cells at the expense of other lineages. Although the effects of mDelta1 on two differentiation systems appeared opposing, as inhibition occurring in one and induction in the other, this can be understood by the unifying concept of generation of diverse cell types from equivalent progenitors. Thus, the present study provided evidence that mammalian Delta participates in intercellular signaling, determining the cell fate in a wide variety of tissues.

Animals↗
PubMed2005

Serrate-Notch signaling defines the scope of the initial denticle field by modulating EGFR activation.

The Drosophila embryonic epidermis has been a key model for understanding the establishment of cell type diversity across a cellular field. During segmental patterning, distinct signaling territories are established that employ either the Hedgehog, Spitz, Serrate or Wingless ligands. How these pathways control segmental pattern is not completely clear. One major decision occurs as cells are allocated to differentiate either smooth cuticle or denticle type cuticle. This allocation is based on competition between Wingless signaling and Spitz, which activates the Epidermal Growth Factor Receptor (EGFR). Here we show that a main role for Serrate-Notch signaling is to adjust the Spitz signaling domain. Serrate accomplishes this task by activating Notch in a discrete domain, the main purpose of which is to broaden the spatially regulated expression of Rhomboid. This adjusts the breadth of the source for Spitz, since Rhomboid is necessary for the production of active Spitz. We also show that the Serrate antagonist, fringe, must temper Notch activity to insure that the activation of the EGFR is not too robust. Together, Serrate and Fringe modulate Notch activation to generate the proper level of EGFR activation. If Serrate-Notch signaling is absent, the denticle field narrows while the smooth cell field expands, as judged by the expression of the denticle field determinant Ovo/Shaven baby. This establishes one important role for the Serrate signaling territory, which is to define the extent of denticle field specification.

Animals↗
PubMed2006

Mechanisms of neurotrophin receptor signalling.

Regulation of cell survival decisions and neuronal plasticity by neurotrophins are mediated by two classes of receptors, Trks (tropomyosin receptor kinases) and p75, the first discovered member of the tumour necrosis factor receptor superfamily. The p75 receptor participates with the TrkA receptor in the formation of high-affinity nerve growth factor-binding sites to promote survival under limiting concentrations of neurotrophins. Activation of Trk receptors leads to increased phosphorylation of Shc (Src homology and collagen homology), phospholipase C-gamma and novel adaptor molecules, such as the ARMS (ankyrin-rich membrane spanning)/Kidins220 protein. Small ligands that interact with G-protein-coupled receptors can also activate Trk receptor kinase activity. Transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects for the treatment of neurodegenerative diseases. Like amyloid precursor protein and Notch, p75 is a substrate for gamma-secretase cleavage. The p75 receptor undergoes an alpha-secretase-mediated release of the extracellular domain followed by a gamma-secretase-mediated intramembrane cleavage. Cleavage of p75 may represent a general mechanism for transmitting signals as an independent receptor and as a co-receptor for other signalling systems.

Adaptor Proteins, Signal Transducing↗
PubMed1976

Complete interruption of the aortic arch. 2. Characteristic angiographic features with emphasis on collateral circulation to the descending aorta.

The angiocardiograms of 17 patients with aortic arch interruption are reviewed to emphasize the variations in arch interruption and origin of the brachiocephalic vessels, and collateral circulation to the descending aorta. Depending on the anatomical type and subtype of arch interruption, collateral flow to the descending aorta in the presence of a stenotic or closed ductus will be dependent on the development of intercostal collaterals and/or the presence of retrograde flow in all brachiocephalic vessels arising from the descending aorta. Familiarity with the potential pathways for collateral circulation may permit differentiation into types and subtypes on chest radiograph. Patients with Type I interruption may have bilateral rib notching if the right subclavian artery originates normally from the innominate artery, but will have rib notching confined to the left side if the origin of the right subclavian artery is aberrant. Type II or Type III interruption patients will have rib notching confined to the right side if the right subclavian has a normal origin, but no rib notching if the origin of the right subclavian artery is aberrant.

Adolescent↗
PubMed2002

A novel epsilon-cleavage within the transmembrane domain of the Alzheimer amyloid precursor protein demonstrates homology with Notch processing.

Proteolytic processing of the transmembrane domain of the amyloid precursor protein (APP) is a key component of Alzheimer's disease pathogenesis. Using C-terminally tagged APP derivatives, we have identified by amino-terminal sequencing a novel cleavage site of APP, at Leu-49, distal to the gamma-secretase site. This was termed -cleavage. Brefeldin A treatment and pulse-chase experiments indicate that this cleavage occurs late in the secretory pathway. The level of -cleavage is decreased by expression of presenilin-1 mutants known to impair Abeta formation, and it is sensitive to the gamma-secretase inhibitors MDL28170 and L-685,458. Remarkably, it shares similarities with site 3 cleavage of Notch-1: membrane topology, cleavage before a valine, dependence on presenilins, and inhibition profile.

Alzheimer Disease↗
PubMed2004

Human papillomavirus type 16 E6 amino acid 83 variants enhance E6-mediated MAPK signaling and differentially regulate tumorigenesis by notch signaling and oncogenic Ras.

Oncogenically high-risk human papillomaviruses (HPVs) are causally associated with the progression of major human neoplasia-like cancers of the cervix. Several studies have defined functions of the key E6 and E7 oncoproteins in epithelial cell immortalization. The roles of these oncogenes in the progression of immortalized epithelial cells to invasive tumors are still poorly understood. Here, we establish a novel link between the E6 oncoprotein and activation of mitogen-activated protein kinase (MAPK) signaling and show that this signaling involves Rap1. We find that activated MAPK signaling cooperates with deregulated Notch1 signaling to recreate features of HPV-driven invasive cervical carcinomas. We extend our analysis to evaluate an E6 (amino acid [aa] 83) variant that has been linked to invasive tumors. The variant enhances MAPK signaling and cooperative transformation with deregulated Notch1 signaling. Unlike E6, this variant surprisingly inhibits oncogenic Ras-mediated transformation. Our data reveal that the quantitative differences in activation of MAPK signaling by E6 and its variant correlate with differences in cooperative transformation with other signaling pathways, thus suggesting that thresholds of MAPK activation may define permissive conditions for other signaling pathways in tumorigenesis. Epidemiological studies have suggested the importance of E6 aa 83 variants in invasive carcinomas; our data support a key deterministic role for this variant in human cervical tumorigenesis. These observations, along with our recent data showing that deregulated Notch signaling activates phosphatidylinositol 3-kinase signaling, strengthen the possibility of the existence of Ras-independent mechanisms to recreate signaling through classical Ras effector pathways.

Animals↗
PubMed1994

The daughterless gene functions together with Notch and Delta in the control of ovarian follicle development in Drosophila.

The daughterless (da) gene in Drosophila encodes a broadly expressed transcriptional regulator whose specific functions in the control of sex determination and neurogenesis have been extensively examined. We describe here a third major developmental role for this regulatory gene: follicle formation during oogenesis. A survey of da RNA and protein distribution during oogenesis reveals a multiphasic expression pattern that includes both germline and soma. Whereas the germline expression reflects da's role in progeny sex determination, the somatic ovary expression of da correlates with the gene's role during egg chamber morphogenesis. Severe, but viable, hypomorphic da mutant genotypes exhibit dramatic defects during oogenesis, including aberrantly defined follicles and loss of interfollicular stalks. The follicular defects observed in da mutant ovaries are qualitatively very similar to those described in Notch (N) or Delta (Dl) mutant ovaries. Moreover, in the ovary da- alleles exhibit dominant synergistic interactions with N or Dl mutations. We propose that all three of these genes function in the same regulatory pathway to control follicle formation.

Animals↗
PubMed1998

Cell signaling in growth and development: the 11th Annual CABM Symposium, October 8-9, 1997.

While many topics were discussed during this symposium, several common themes emerged from the presentations. First, it is increasingly evident that regulation of ligand-receptor interactions is complex and can occur at nearly every conceivable step, including protein processing for release from or tethering to the cell surface, diffusibility through tissues, binding to soluble inhibitors, and competition with antagonists for receptor binding. In particular, the availability of these regulatory steps allows for a range of potential mechanisms by which ligand signaling can be modulated by other protein factors, such as in the case of fringe and its effects on signaling through the Notch receptor. Secondly, a major area of effort in the signaling field will increasingly focus on how cells integrate the signals received from different pathways to coordinate specific developmental responses. For example, as McMahon pointed out, the major signaling pathways that govern the anterior-posterior, dorsal-ventral, and proximal-distal axes of the developing limb bud have now been identified, yet it is completely unclear how these pathways interact to produce positional information in three dimensions. Thirdly, biochemical and structural investigations are now providing insights into the nature of the feedback mechanisms that regulate the strength and duration of activated signals, and how in some cases, these feedback loops can also provide a 'memory' of the signaling response, such as in the case of the adaptation found in bacterial chemotaxis. Finally, the structural analyses of signal transducing molecules remind us of the necessity to understand the mechanistic details of how active and inactive states are maintained, particularly since distant protein modifications can lead to global conformational changes that alter protein activity. These and other general insights underscore the value of broad-based meetings that cut across a range of disciplines and methodologies, such as this CABM symposium, and provide ideas for future directions of investigation.

Animals↗
PubMed2005

Endocytic control of epithelial polarity and proliferation in Drosophila.

Intracellular protein transport is a key factor in epithelial cell polarity. Here we report that mutations in two core components of the vesicle trafficking machinery - a syntaxin and a Rab protein - cause an expansion of the apical membrane domain of Drosophila melanogaster epithelia; this polarity defect is coupled with overproliferation to form neoplastic tumours. Surprisingly, these proteins are associated with the endocytic, and not the exocytic, pathway. The syntaxin Avalanche (Avl) localizes to early endosomes, and loss of avl results in the cellular accumulation of specific membrane proteins, including the Notch signalling receptor and the polarity determinant Crumbs (Crb). Protein accumulation results from a failure in endosomal entry and progression towards lysosomal degradation; these and other avl phenotypes are also detected in Rab5 null mutant cells. Overexpression of Crb alone is sufficient to induce overproliferation of wild-type imaginal tissue, suggesting that polarity alterations in avl and Rab5 mutants directly contribute to tumour formation. Our findings reveal a critical and specific role for endocytic traffic in the control of both apico-basal polarity and cell proliferation.

Animals↗