WO1990015869A1 - Systemes transgeniques d'examen de la peau - Google Patents

Systemes transgeniques d'examen de la peau Download PDF

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Publication number
WO1990015869A1
WO1990015869A1 PCT/US1990/003510 US9003510W WO9015869A1 WO 1990015869 A1 WO1990015869 A1 WO 1990015869A1 US 9003510 W US9003510 W US 9003510W WO 9015869 A1 WO9015869 A1 WO 9015869A1
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WIPO (PCT)
Prior art keywords
transgenic animal
skin
reporter gene
gene
sequence
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Application number
PCT/US1990/003510
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English (en)
Inventor
Thomas E. Shenk
Arnold J. Levine
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Embryogen Corporation
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Publication date
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Publication of WO1990015869A1 publication Critical patent/WO1990015869A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5014—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing toxicity
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6897—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids involving reporter genes operably linked to promoters
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/20—Animal model comprising regulated expression system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0393—Animal model comprising a reporter system for screening tests

Definitions

  • the present invention relates to transgenic non-human animals which can be used as model skin-testing systems. 5 Recombinant DNA techniques are used to produce novel genetic constructs which confer upon their transgenic hosts the ability to respond, in a quantifiable way, to physical or chemical stimuli applied to their skin.
  • the transgenic skin-testing system offers a means for identifying effective ⁇ skin-protective (i.e. ultraviolet light blocking) agents and also provides methods for evaluating the effects of ultraviolet radiation, chemical and cosmetic compounds on the skin, skin pathology, and aging.
  • the epidermis consists of stratified squamous epithelium. Cells which originate in the deepest layer, or stratum germinativu , migrate to the surface, or uppermost 5layer, to replace cells which are continually sloughed off.
  • keratinized cells During migration, these cells accumulate keratin; at the skin surface, keratinized cells form what appears to be a fibrous, rather than a cellular, layer called the stratum corneum.
  • Specialized epidermal cells, called melanocytes, 0 do not undergo keratmization but instead produce the skin pigment, melanin.
  • Additional cell types found in the epidermis include Merkel cells, which serve a sensory function, and Langerhans cells, which are components of the immune system. The epidermis gives rise to nails, hair, 5 sebaceous glands, sweat glands, and the parenchyma of mammary glands.
  • the dermis consists largely of dense, irregular connective tissue. It contains nerve endings, blood vessels, and lymphatic vessels. 5
  • the Cab gene complex of wheat (Lamppa et al., supra) has been introduced into transgenic tobacco plants, in which Cab continued to be expressed in a light-regulated manner (Lamppa et al., 1985, Nature
  • HSV human immunodeficiency virus
  • LTR viral long-terminal repeated sequence
  • CAT chloramphenicol aceytl transferase
  • TRANSGENIC ANIMALS The term "transgenic animals” refers to non-human animals which have incorporated a foreign gene into their 5 genome; because this gene is present in germ line tissues, it is passed from parent to offspring. Exogenous genes are introduced by microcapillary injection into single-celled embryos (Gordon et al., 1980, Proc. Natl. Acad. Sci. U.S.A.
  • the invention is directed to a transgenic non-human animal skin-testing system. Briefly described, recombinant DNA techniques are used to produce novel genetic constructs which confer upon their transgenic hosts the ability to respond, in a quantifiable way, to physical or chemical stimuli applied to their skin.
  • the genetic constructs of the invention may encode a variety of promoter and/or enhancer sequences in combination with a number of reporter genes.
  • a recombinant DNA construct may comprise a light sensitive, topically-activated or skin-specific promoter in combination with a colorimetric or tumorigenic reporter gene.
  • Transgenic non-human animals which have incorporated such a construct into their germ line would provide powerful systems for evaluating the effects of physical (i.e., u.v. light) or chemical agents and the efficacy of protective agents (i.e., sunscreen, anti-aging formulations) on the skin, and may also supply model systems for various skin pathologies including malignancy (i.e., melanoma) , psoriasis, allergy, and aging.
  • malignancy i.e., melanoma
  • psoriasis psoriasis
  • FIGURE 1 Plasmid pHIV-LTRl/lac Z carries the ⁇ - galactosidase gene under the control of the HIV-LTR promoter in addition to the gene for ampicillin resistance. 5. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention is directed to transgenic non- human animal skin-testing systems in which recombinant genetic constructs are used to confer upon transgenic animals the ability to respond, in a quantifiable way, to physical or chemical stimuli applied to their skin. This capability arises from the use of promoter elements that may be selectively activated in skin, either due to tissue- specificity or induction by physical (i.e., ultraviolet light) or chemical topically active substances. According '"to the invention, these skin selective promoters are combined with a reporter gene associated with a readily identifiable product.
  • transgenic animal The animal carrying in its germ line a foreign piece of DNA, termed a transgene, is called a transgenic animal.
  • a transgenic animal One method for the creation of transgenic mice for producing test animals is described below. 0 In general, the scheme presently employed to produce transgenic mice involves the following: male and female mice are mated at midnight. Twelve hours later, the female is sacrificed and the fertilized eggs are removed from the uterine tubes. At this time, the pronuclei have not yet 5 fused and it is possible to visualize them in the light microscope.
  • Foreign DNA is then microinjected (100-1000 molecules per egg) into a pronucleus. Shortly thereafter fusion of the pronuclei (a pronucleus or the male pronucleus) occurs and, in some cases, foreign DNA inserts ⁇ Lnto (usually) one chromosome of the fertilized egg or zygote.
  • the zygote is then implanted into a pseudo-pregnant female mouse (previously mated with a vasectomized male) where the embryo develops for the full gestation period of 20-21 days.
  • the surrogate mother delivers these mice and by %our weeks the pups are weaned from the mother.
  • mice To test these mice for the presence of foreign DNA, a portion of the tail (a dispensable organ) is removed and the DNA extracted. DNA-DNA hybridization (in a dot blot, slot blot or Southern blot test) is employed to determine whether the mice carry he foreign DNA. Of the eggs injected, on average 10% develop properly and produce mice. Of the mice born, on average one in four (25%) are transgenic for an overall efficiency of 2.5%. Once these mice are bred they pass along the foreign gene in a normal (Mendelian) fashion linked to a mouse chromosome. Mating two homozygous mice with the transgenic DNA means 100% of the offspring carry two copies of the transgene.
  • mice carry tandemly repeated copies of the foreign gene (from 3-80 copies) at one chromosomal location or site.
  • mice including hairless mice; guinea pigs, 0 including albino guinea pigs; rabbits and pigs, to name but a few, may provide useful transgenic skin-testing systems.
  • any method known in the art may be used to produce transgenic animals, including but not limited to, 5 microinjection, transfection of DNA, sperm transfer and electroporation.
  • a skin-selective 5 promoter is combined with a suitable reporter gene (see infra) to create a genetic construct for introduction into transgenic animals.
  • a suitable reporter gene see infra
  • skin selective promoter should be construed to mean any DNA sequence that will control the expression of its associated reporter gene in '"skin and it may or may not also control the expression of its reporter gene in other tissues; this includes promoter sequences which are skin-selective because they are indu ⁇ ible by stimuli which may be applied to skin. For example a light-inducible promoter could be activated in any
  • the promoter behaves as a skin-selective promoter.
  • Activity of the skin selective promoter is not restricted to any particular cell type, so that the term "skin-selective promoter" can apply to any one, or any combination, of the 0cell types present i.n skm. (includi.ng, but not li.mi.ted to the cells of the epidermis and the de ⁇ rtis, such as epithelial cells, keratinocytes, melanocytes, or cells of the immune system) .
  • the skin selective 5promoter can be manipulated to result in either an increase, or decrease of reporter gene transcription.
  • Appropriate promoter elements would include light- inducible promoters, including, but not limited to the HIV- LTR (Valerie et al., 1988, Nature 333:78-81) the Cab-1- 0 associated regulatory region (Lamppa et al., 1985, Nature
  • promoters which are inducible by chemical stimuli may be used according to the invention, for example, the HIV-LTR
  • promoters are responsive to phorbol esters, for example, the c-jun
  • TPA tumor promotion activity
  • promoter elements which are endogenously skin-specific may be used according to the invention.
  • Eukaryotic cellular and viral promoter-elements, and even portions of prokaryotic promoter-operator elements may be employed.
  • the skin-selective promoter may be combined with any reporter gene that has a readily identifiable product according to the invention.
  • the sk. -selecti.ve promoter may be combined with a reporter gene with a visually or autoradiographically detectable product.
  • the HIV-LTR is combined with the / 9-galactosidase (j ⁇ -gal) gene in transgenic
  • a skin-selective promoter may be associated with the gene for luciferase (Ow et al., 1986, Science 234:856- 30
  • luciferase is selectively produced in the transgenic animals skin; exposure to luciferin (i.e. topically applied) may result in emission of light.
  • the skin- selective promoter may be combined with a reporter gene associated with a chemically detectable product including, but not limited to, ,9-glucuronidase (Jefferson et al., 1986, Proc. Natl. Acad. Sci. U.S.A. £:8447-8451) ; chloramphenicol acetyltransferase (Gorman et al., 1982, Mol. Cell. Biol. 2 1044-1051) , and xanthine-guanine phosphoribosyltransferase 5 (Mulligan and Berg, 1980, Science 209:1422-1427) .
  • a reporter gene associated with a chemically detectable product including, but not limited to, ,9-glucuronidase (Jefferson et al., 1986, Proc. Natl. Acad. Sci. U.S.A. 85:8447-8451) ; chloramphenicol acetyltransferase (Gorman e
  • the skin- selective promoter may be combined with a reporter gene with a biologically active product.
  • this product may be tumorigenic
  • the O reporter gene may be an oncogene. Any oncogene whether previously described or yet to be discovered could potentially be utilized in the assays described in the subsections below.
  • Known oncogenes which could be utilized include but are not limited to those derived from DNA tumor
  • 15viruses e.g., T antigen genes from SV40 or polyoma viruses
  • E1A and E1B genes from adenoviruses and other genes known to have tumorigenic potential derived from papillomaviruses and herpes viruses; reviewed in Bishop, 1985, 1985, Cell
  • retroviruses e.g., v-abl, v-fes, v-fps, v-fgr, * 0v-src, v-erbA, v-erbB, v-fms, v-ros, v-yes, v-mos, v-ras, v-fos, v-myb, v-myc, v-ski, v-sis, v-rel, v-kit, v-jun, v- ets; reviewed in Bishop, 1985, Cell 4 ⁇ :23-38) ; cellular proto-oncogenes corresponding to the viral oncogenes, activated cellular oncogenes corresponding to viral 5oncogenes, or cellular oncogenes for which no viral counterpart has yet been described (e.g., c-neu, Hung et al., 1986, Proc. Nat. Acad. "
  • the present invention provides methods for evaluating the effects of physical or chemical agents on the skin, offers reliable methods for determining the efficacy of skin-protective compounds or devices, and allows for the development of novel animal model systems for various human skin pathologies.
  • the present invention can be used to test the efficacy of skin-protective agents.
  • the invention can be used to quantitate the ability of sunscreen agent to protect skin against the deleterious effects of ultraviolet radiation.
  • an ultraviolet light-inducible promoter DNA sequence may be combined with the ⁇ - ' galactosidase reporter gene and introduced into transgenic mice. If these mice were exposed to ultraviolet light and then to X-gal, a chromogenic substrate for 9-galactosidase, their skin, including their tails, would turn blue; an effective sunscreen would prevent the development of blue
  • promoters m. ducible by compounds that damage the skin hereafter referred to as stress-inducing chemicals
  • appropriate reporter genes could be introduced into transgenic animals which could be used to determine the effectiveness of protective agents against
  • stress-inducing chemicals i.e., DNA damaging agents
  • transgenic skin-testing systems may be used as reliable tests to identify skin-damaging agents.
  • transgenic animals which carry exogenous DNA comprising a stress-
  • 25chemical mducible promoter and suitable reporter gene could be used to screen cosmetics for stress-chemical, i.e. DNA damaging, activity.
  • mutations could be introduced into the promoter/reporter gene construct prior to introduction into transgenic animals. These mutated 30 constructs would require reverse mutation in order to express reporter gene product, and thus would provide a reliable method for testing for mutagenizing agents.
  • a complete description of transgenic testing systems for mutagens and carcinogens is contained in U. S. patent application serial No. 132,383, filed December 15, 1987, which is incorporated by reference in its entirety herein.
  • the present invention provides model systems for various skin diseases.
  • a skin-selective promoter sequence may be combined with an oncogene and introduced into transgenic animals. Animals carrying this transgene may develop skin tumors in response to promoter induction; such animals may also exhibit proliferative diseases of the skin, i.e. psoriasis.
  • the ' HIV-LTR may be combined with the gene encoding simian virus 40 T antigen.
  • a skin selective promoter may be combined with a biologically active substance, such as a lymphokine, and introduced into transgenic animals which may
  • regulatory sequences which are active only in cells of the immune system i.e. the immunoglobulin gene control region as described by Grosschedl et al., 1984, Cell 3_8:647-658; Adames et al., 1985, Nature 318:533-538; 0 Alexander et al. , 1987, Mol. Cell. Biol. 2:1436-1444) could be combined with a light-inducible promoter and a reporter gene; thus the immune cells of the transgenic animals would produce reporter gene product only in response to light, thereby, only when localized to the skin.
  • a considerable utility of the present invention resides in its ability to engender reliable, quantifiable assays for skin testing.
  • Many of the present methods which utilize animal models for skin testing are based on the measurement of tissue damage, i.e., sunscreen 0 tests and the Draize test.
  • the present invention provides more sensitive assays which may detect a harmful stimulus before damage is done; for example, if a light-activated promoter were combined with ⁇ -galactosidase ( -gal) in a transgenic animal, exposure to ultraviolet light could D induce ⁇ -gscl before a painful sunburn could arise.
  • the quantitative nature of transgenic skin-testing systems would be likely to reduce the number of animals presently used in research, in which large numbers are necessitated by wide fluctuations in experimental results.
  • the present invention provides for an accurate time-efficient, cost-effective, and hopefully more humane method of animal skin-testing.

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Abstract

Des animaux transgéniques non humains peuvent être utilisés comme systèmes modèles d'examen de la peau. On utilise des techniques de recombinaison d'ADN afin de produire de nouvelles structures génétiques qui confèrent à leurs hôtes transgéniques la capacité de répondre de manière quantifiable à des stimuli physiques ou chimiques appliqués à leur peau. Le système transgénique d'examen de la peau permet d'identifier des agents efficaces de protection de la peau (par exemple des agents de protection contre la lumière ultraviolette) et des procédés d'évaluation des effets de rayonnements ultraviolets, de composés chimiques et cosmétiques sur la peau, sur la pathologie et le vieillissement de la peau.
PCT/US1990/003510 1989-06-19 1990-06-18 Systemes transgeniques d'examen de la peau WO1990015869A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023533A1 (fr) * 1992-05-08 1993-11-25 Exemplar Corporation Test in vivo de medicaments anti-neoplasiques
WO1997006277A1 (fr) * 1995-08-09 1997-02-20 The Regents Of The University Of California Procedes destines a la prospection systematique de medicaments
WO1998006874A1 (fr) * 1995-08-09 1998-02-19 The Regents Of The University Of California Systemes pour generer et analyser des matrices de signaux de sortie de type stimulus-reponse
US5945576A (en) * 1996-04-05 1999-08-31 Brigham & Women's Hospital, Inc. Mouse model of psoriasis
US6326140B1 (en) 1995-08-09 2001-12-04 Regents Of The University Of California Systems for generating and analyzing stimulus-response output signal matrices

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4736866A (en) * 1984-06-22 1988-04-12 President And Fellows Of Harvard College Transgenic non-human mammals

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
US4736866A (en) * 1984-06-22 1988-04-12 President And Fellows Of Harvard College Transgenic non-human mammals
US4736866B1 (en) * 1984-06-22 1988-04-12 Transgenic non-human mammals

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF VIROLOGY, (Washington, USA), Volume 63, Number 11, issued November 1989, STEIN et al., "UV-induced transcription from the human immunodeficiency virus type 1 (HIV-1), long terminal repeat and UV-induced secretion of an extracellular factor that induced HIV-1 transciption in non-irradiated cells", pages 4540-4544, see the entire document. *
MOLECULAR AND CELLULAR BIOLOGY, Volume 9, Number 11, issued November 1989, (Washington, USA), STEIN et al., "UV-induced DNA damage is an intermediate step in UV-induced expression of human immunodeficiency virus type 1, collagenase, C-fos and metallothionein", pages 5169-5181, see the entire document. *
NATURE, Volume 310, issued 12 July 1984, (London, UK), HERRERA-ESTRELLA et al., "Light-inducible and chloroplast-associated expression of a chimeric gene introduced into Nicotiana tabacum using a Ti plasmid vector", pages 115-120, see the entire document. *
NATURE, Volume 335, issued 05 May 1988, (London, UK), VALERIE et al., "Activation of human immunodeficiency virus type 1 by DNA damage in human cells", pages 78-81, see the entire document. *
NATURE, Volume 335, issued 13 October 1988, (London, UK), VOGEL et al., "The HIV tat gene induces dermal lesions resembling Kaposi's sarcoma in transgenic mice", pages 606-611, see the entire document. *
SCIENCE, Volume 235, issued 23 January 1987, (Washington, USA), GORING et al., "In situ detection of Beta-galactosidase in lenses of transgenic mice with - crystallin/lacZ gene", pages 456-458, see the entire document. *
THE EMBO JOURNAL, Volume 7, Number 7, issued 1988, (Oxford, UK), CASTRESANA et al., "Both positive and negative regulating elements mediate expression of a photoregulated CAB gene from Nicotiana plumbaginifolia", pages 1929-1936, see the entire document. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993023533A1 (fr) * 1992-05-08 1993-11-25 Exemplar Corporation Test in vivo de medicaments anti-neoplasiques
WO1997006277A1 (fr) * 1995-08-09 1997-02-20 The Regents Of The University Of California Procedes destines a la prospection systematique de medicaments
WO1998006874A1 (fr) * 1995-08-09 1998-02-19 The Regents Of The University Of California Systemes pour generer et analyser des matrices de signaux de sortie de type stimulus-reponse
US5777888A (en) * 1995-08-09 1998-07-07 Regents Of The University Of California Systems for generating and analyzing stimulus-response output signal matrices
US6326140B1 (en) 1995-08-09 2001-12-04 Regents Of The University Of California Systems for generating and analyzing stimulus-response output signal matrices
US6574568B2 (en) 1995-08-09 2003-06-03 Regents Of The University Of California Systems for generating and analyzing stimulus-response output signal matrices
US5945576A (en) * 1996-04-05 1999-08-31 Brigham & Women's Hospital, Inc. Mouse model of psoriasis

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