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Article: Making mechanistic connections between cell signaling pathways and pathological endpoints.

Davis, Myrtle A

2004 Volume 32 Suppl 1, Page(s) 131–135

Abstract: Cell signaling is a term used to describe a complex interactive system of signals that act to regulate or mediate a cellular response. Therapies that target cell signaling pathways have the potential to effectively reverse molecular deregulation ... ...

Abstract	Cell signaling is a term used to describe a complex interactive system of signals that act to regulate or mediate a cellular response. Therapies that target cell signaling pathways have the potential to effectively reverse molecular deregulation underlying disease. The inherent complexity of cell signaling presents a major challenge to designing such therapies however, because perturbation of pathways has the potential to produce dramatic adverse effects. Pathologists are in the primary position of detecting adverse responses in drug development and are essential members of teams whose goal is to determine the mechanisms underlying tissue responses. The pathologist therefore will be expected to integrate morphologic interpretation with data obtained from several laboratory-based methods and data derived from novel technologies. Approaches being used include several in silico tools that provide access to public databases and signal pathway visualization that can serve to focus on key mechanistic hypotheses. The main objective of this article is to discuss a basic mechanistic approach and methods that can be used to associate modulation of cell signaling pathways with pathologic endpoints. The approach suggested begins with diagnostic pathology and uses global gene expression analysis in conjunction with transcription factor profiling and confirmatory protein technologies, to elucidate pathways relevant to the biological mechanism. Another important objective is to highlight the use of in silico technologies to prioritize laboratory efforts and focus these efforts on key hypotheses.
MeSH term(s)	Animals ; Blotting, Western ; Cells/metabolism ; Gene Expression Regulation ; Humans ; Lasers ; Models, Biological ; Oligonucleotide Array Sequence Analysis ; Pathology ; Phosphotransferases/metabolism ; Promoter Regions, Genetic ; Signal Transduction
Chemical Substances	Phosphotransferases (EC 2.7.-)
Language	English
Publishing date	2004-03
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	841009-4
ISSN	0192-6233
ISSN	0192-6233
DOI	10.1080/01926230490424923
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Article: Remembering Benjamin Franklin Trump.

Klaunig, James E / Davis, Myrtle A

Veterinary pathology

2008 Volume 45, Issue 5, Page(s) 611–612

MeSH term(s)	History, 20th Century ; History, 21st Century ; Pathology ; United States
Language	English
Publishing date	2008-09
Publishing country	United States
Document type	Biography ; Historical Article ; Journal Article ; Portraits
ZDB-ID	188012-3
ISSN	1544-2217 ; 0300-9858
ISSN (online)	1544-2217
ISSN	0300-9858
DOI	10.1354/vp.45-5-611
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Book: Apoptosis methods in pharmacology and toxicology

Davis, Myrtle A

approaches to measurement and quantification

(Methods in pharmacology and toxicology)

2002

Author's details	edited by Myrtle A. Davis
Series title	Methods in pharmacology and toxicology
MeSH term(s)	Apoptosis/physiology ; Cytological Techniques
Language	English
Size	xiv, 156 p. :, ill.
Publisher	Humana
Publishing place	Totowa, N.J
Document type	Book
ISBN	9780896038905 ; 0896038904
Database	Catalogue of the US National Library of Medicine (NLM)

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Article: The tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) provokes a prolonged morphologic response and ERK activation in Tsc2-null renal tumor cells.

Kolb, Todd M / Davis, Myrtle A

Toxicological sciences : an official journal of the Society of Toxicology

2004 Volume 81, Issue 1, Page(s) 233–242

Abstract: Loss of tumor suppressor function dramatically alters the cellular response to chemicals. The phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), stimulates cell proliferation through rapid activation of protein kinase C (PKC), ... ...

Abstract	Loss of tumor suppressor function dramatically alters the cellular response to chemicals. The phorbol ester tumor promoter, 12-O-tetradecanoylphorbol 13-acetate (TPA), stimulates cell proliferation through rapid activation of protein kinase C (PKC), followed by gradual degradation of the kinase. TPA also activates the GTPase Rap1 in some cell types. The tumor suppressor protein Tsc2 has a proposed GTPase activating protein (GAP) function for Rap1, providing a common mechanistic target for Tsc2 and TPA. We compared the cellular response of Tsc2-null (ERC-18) and Tsc2-competent (NRK-52E) renal epithelial cells to TPA treatment. Treatment of ERC-18 cells with 100 ng/ml TPA for 24 h resulted in loss of cell-cell contact, retraction of the cell periphery and rounding. These changes were reversed 1 h after treatment in NRK-52E cells and were apparent 24 h after treatment of ERC-18 cells. Expression of Tsc2 in ERC-18 cells abrogated the prolonged morphologic response. TPA treatment rapidly increased phosphorylation of ERK, a reported downstream effector of both PKC and Rap1, in ERC-18 cells, but induced weak Rap1 activation. TPA-induced ERK phosphorylation was prolonged in ERC-18 cells compared to NRK-52E cells and expression of Tsc2 in ERC-18 cells did not inhibit prolonged ERK activation. The selective PKC inhibitor, bisindolylmaleimide VIII, however, inhibited TPA-induced changes in morphology and ERK activation. These results imply that TPA-induced changes in morphology and ERK activation are mediated primarily through PKC and not Rap1 in renal epithelial cells. These data also imply that Tsc2 expression modulates TPA-induced changes in renal epithelial cell morphology via an ERK-independent mechanism.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Carcinogens/toxicity ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Cell Death/drug effects ; Cell Division/drug effects ; Cell Line, Tumor ; Enzyme Activation/drug effects ; Immunoblotting ; Immunohistochemistry ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Mitogen-Activated Protein Kinases/metabolism ; Phosphorylation ; Plasmids/genetics ; Protein Kinase C/metabolism ; Protein Kinase C-alpha ; Rats ; Repressor Proteins/genetics ; Telomere-Binding Proteins/genetics ; Tetradecanoylphorbol Acetate/toxicity ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins
Chemical Substances	Carcinogens ; Repressor Proteins ; TERF2IP protein, human ; TSC2 protein, human ; Telomere-Binding Proteins ; Tsc2 protein, rat ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; Protein Kinase C (EC 2.7.11.13) ; Protein Kinase C-alpha (EC 2.7.11.13) ; Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Tetradecanoylphorbol Acetate (NI40JAQ945)
Language	English
Publishing date	2004-06-03
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfh183
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Article ; Online: Comparative uterotrophic effects of endoxifen and tamoxifen in ovariectomized Sprague-Dawley rats.

Schweikart, Karen M / Eldridge, Sandy R / Safgren, Stephanie L / Parman, Toufan / Reid, Joel M / Ames, Matthew M / Goetz, Matthew P / Davis, Myrtle A

Toxicologic pathology

2014 Volume 42, Issue 8, Page(s) 1188–1196

Abstract: Endoxifen (4-hydroxy-N-desmethyl-tamoxifen), one of the major active metabolites of tamoxifen, has substantially greater estrogen antagonist properties and antiproliferative effects in breast tumor cells than tamoxifen, a mixed estrogen agonist/ ... ...

Abstract	Endoxifen (4-hydroxy-N-desmethyl-tamoxifen), one of the major active metabolites of tamoxifen, has substantially greater estrogen antagonist properties and antiproliferative effects in breast tumor cells than tamoxifen, a mixed estrogen agonist/antagonist. An associated risk of endometrial cancer and hyperplasia has been linked to the estrogen agonist properties of tamoxifen. We evaluated endoxifen using a classic uterotrophic effects method. Rats were given endoxifen or tamoxifen orally for 3 days. Estradiol was the positive control. Endoxifen and tamoxifen plasma levels exceeded those previously observed clinically. Uterine weight was 3-fold higher in the estradiol group than in the tamoxifen or endoxifen groups, which did not differ from vehicle controls. Tamoxifen and endoxifen caused a greater increase in luminal epithelial cell height than estradiol. Both tamoxifen and endoxifen produced an increase in the stromal BrdU labeling index (LI) that was ≤ estradiol and inversely related to dose, but did not affect luminal epithelial cell BrdU LI. As expected, estradiol increased luminal epithelial cell proliferation. These results indicate that endoxifen induces uterotrophic effects, but is less potent than estradiol in eliciting these effects. Given prior preclinical observations that endoxifen has superior antitumor activity than tamoxifen, the observations of similar uterine effects suggest that the endoxifen risk/benefit ratio may be superior to tamoxifen.
MeSH term(s)	Animals ; Cell Proliferation/drug effects ; Endometrium/chemistry ; Endometrium/drug effects ; Female ; Histocytochemistry ; Hypertrophy/chemically induced ; Organ Size/drug effects ; Ovariectomy ; Rats ; Rats, Sprague-Dawley ; Tamoxifen/analogs & derivatives ; Tamoxifen/toxicity ; Uterus/chemistry ; Uterus/drug effects
Chemical Substances	Tamoxifen (094ZI81Y45) ; 4-hydroxy-N-desmethyltamoxifen (46AF8680RC)
Language	English
Publishing date	2014-03-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	841009-4
ISSN	1533-1601 ; 0192-6233
ISSN (online)	1533-1601
ISSN	0192-6233
DOI	10.1177/0192623314525688
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Article: Tsc2 expression increases the susceptibility of renal tumor cells to apoptosis.

Kolb, Todd M / Duan, Ling / Davis, Myrtle A

Toxicological sciences : an official journal of the Society of Toxicology

2005 Volume 88, Issue 2, Page(s) 331–339

Abstract: Although the precise role for the tuberous sclerosis complex-2 tumor suppressor gene (Tsc2) in tumor suppression is not clear, many studies have implicated Tsc2 in the regulation of cell differentiation, cell cycle control, GTPase activity, transcription, ...

Abstract	Although the precise role for the tuberous sclerosis complex-2 tumor suppressor gene (Tsc2) in tumor suppression is not clear, many studies have implicated Tsc2 in the regulation of cell differentiation, cell cycle control, GTPase activity, transcription, polycystin-1 localization, and translation initiation. We propose that Tsc2 also increases susceptibility to apoptosis, and that this functional role may contribute to the tumor suppressor activity of Tsc2. We previously characterized the apoptotic response of a Tsc2-null renal tumor cell line (ERC-18) to the tumor promoter okadaic acid (OKA). In the present study, we expressed Tsc2 in ERC-18 cells and compared the effect of Tsc2 expression on apoptotic induction. Tsc2 expression increased the susceptibility of ERC-18 cells to apoptosis induced by OKA and the phosphatidylinositol-3' kinase inhibitor, LY294002. In addition, Tsc2 expression abrogated OKA-induced cell detachment of ERC-18 cells. These results indicate that the OKA-induced, caspase-independent detachment previously observed in ERC-18 cells is Tsc2-dependent, and may support an additional role for the Tsc2 in regulating cell adhesion.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Apoptosis/genetics ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/metabolism ; Carcinoma, Renal Cell/pathology ; Caspase 3 ; Caspases/metabolism ; Cell Adhesion/drug effects ; Cell Adhesion/genetics ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Chromones/toxicity ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/toxicity ; Gene Expression Regulation, Neoplastic/drug effects ; Kidney Neoplasms/drug therapy ; Kidney Neoplasms/metabolism ; Kidney Neoplasms/pathology ; Morpholines/toxicity ; Okadaic Acid/toxicity ; Rats ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins/deficiency ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Chromones ; Enzyme Inhibitors ; Morpholines ; Tsc2 protein, rat ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; Okadaic Acid (1W21G5Q4N2) ; 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (31M2U1DVID) ; Casp3 protein, rat (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2005-09-08
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1420885-4
ISSN	1096-0929 ; 1096-6080
ISSN (online)	1096-0929
ISSN	1096-6080
DOI	10.1093/toxsci/kfi310
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Article: Biochemical and morphological events during okadaic acid-induced apoptosis of Tsc2-null ERC-18 cell line.

Kolb, Todd M / Chang, Seung H / Davis, Myrtle A

Toxicologic pathology

2002 Volume 30, Issue 2, Page(s) 235–246

Abstract: Several tumor suppressor genes have been shown to regulate cellular susceptibility to proliferation or apoptotic cell death. An essential first step in studies with the long-range goal of determining the effect of a tumor suppressor gene on cellular ... ...

Abstract	Several tumor suppressor genes have been shown to regulate cellular susceptibility to proliferation or apoptotic cell death. An essential first step in studies with the long-range goal of determining the effect of a tumor suppressor gene on cellular susceptibility to apoptosis is careful characterization of the cell's response to an apoptotic stimulus. The goals of this study were to characterize the apoptotic response of a tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene-null cell line, to establish valid biochemical events that can be used as apoptosis markers, and to determine how these events correlate with apoptosis-specific morphologic changes. For characterization of apoptosis, we treated Tsc2-null renal epithelial tumor cells (ERC-18) with okadaic acid (OKA, 0.1-0.25 microM), and measured the biochemical and morphologic events during the apoptotic response. Electron microscopic and immunocytochemical evaluation showed an early loss of microvilli and a loss of vinculin and talin staining from focal adhesions within 1 hour. During the first 2 hours of treatment with 0.25 microM OKA, ERC-18 cells rounded and approximately 50% detached from the culture vessel with minimal membrane bleb formation. Phosphatidylserine externalization, chromatin margination and fragmentation, cytochrome C release, and caspase-3 and -7 cleavage were evident at 6 hours. Maximal membrane bleb formation occurred between 6 and 10 hours. Cells progressed to secondary oncotic necrosis between 10 and 24 hours of OKA treatment. Almost all cells had an oncotic phenotype after 24 hours, and 17.5% lost cell membrane integrity. A small subpopulation (< or = 5%) of OKA-treated cells underwent primary oncotic necrosis within 6 hours. Interestingly, the caspase-3 and -7 inhibitor Z-DEVD-FMK did not inhibit or delay OKA-induced apoptosis in these cells. Our results suggest a complex apoptotic model involving 2 or more potentially parallel death pathways. Although caspase-3 and -7 cleavage occurs during apoptosis in this model, this cleavage may not independently regulate cell death in ERC-18 cells. Therefore, measurement of apoptosis in this model requires analysis of both biochemical and morphologic events.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Caspases/metabolism ; Cytochrome c Group/metabolism ; Kidney Neoplasms/pathology ; Okadaic Acid/toxicity ; Oligopeptides/pharmacology ; Phosphatidylserines/metabolism ; Phosphorylation ; Rats ; Repressor Proteins/physiology ; Talin/analysis ; Tuberous Sclerosis Complex 2 Protein ; Tumor Cells, Cultured ; Tumor Suppressor Proteins ; Vinculin/analysis
Chemical Substances	Cytochrome c Group ; Oligopeptides ; Phosphatidylserines ; Repressor Proteins ; Talin ; Tsc2 protein, rat ; Tuberous Sclerosis Complex 2 Protein ; Tumor Suppressor Proteins ; benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone ; Vinculin (125361-02-6) ; Okadaic Acid (1W21G5Q4N2) ; Caspases (EC 3.4.22.-)
Language	English
Publishing date	2002-03
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	841009-4
ISSN	0192-6233
ISSN	0192-6233
DOI	10.1080/019262302753559579
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Article ; Online: Chronic microcystin exposure induces hepatocyte proliferation with increased expression of mitotic and cyclin-associated genes in P53-deficient mice.

Clark, Shawn P / Ryan, Timothy P / Searfoss, George H / Davis, Myrtle A / Hooser, Stephen B

Toxicologic pathology

2008 Volume 36, Issue 2, Page(s) 190–203

Abstract: Homozygous p53 deficient knockout mice were used to assess the role of p53 in tumor promotion by the protein phosphatase inhibitor and hepatic tumor promoter microcystin-LR (MCLR). More than 50% of human cancers bear mutations in the p53 gene, and in ... ...

Abstract	Homozygous p53 deficient knockout mice were used to assess the role of p53 in tumor promotion by the protein phosphatase inhibitor and hepatic tumor promoter microcystin-LR (MCLR). More than 50% of human cancers bear mutations in the p53 gene, and in particular, p53 tumor suppressor gene mutations have been shown to play a major role in hepatocarcinogenesis. Trp53 homozygous (inactivated p53) and age-matched wild-type control mice were assigned to vehicle or MCLR-treated groups. MCLR or saline was administered daily for up to 28 days. RNA from the 28-day study was hybridized onto Mouse Genome GeneChip arrays. Selected RNA from 28 days and earlier time points was also processed for quantitative polymerase chain reaction (PCR). Livers from the 28-day, Trp53-deficient, MCLR group displayed greater hyperplastic and dysplastic changes morphologically and increases in Ki-67 and phosphohistone H3 (mitotic marker) immunoreactivity. Gene-expression analysis revealed significant increases in expression of cell-cycle regulation and cellular proliferation genes in the MCLR-treated, p53-deficient mutant mice compared to controls. These data suggest that regulation of the cell cycle by p53 is important in preventing the proliferative response associated with chronic, sublethal microcystin exposure, and therefore, conclude that p53 plays an important role in MCLR-induced tumor promotion.
MeSH term(s)	Animals ; Bacterial Toxins/toxicity ; Carcinogens/toxicity ; Cell Cycle/genetics ; Cell Proliferation/drug effects ; Gene Expression/drug effects ; Gene Expression Profiling ; Gene Silencing ; Genes, p53/genetics ; Hepatocytes/drug effects ; Hepatocytes/metabolism ; Liver/drug effects ; Liver/metabolism ; Male ; Mice ; Mice, Knockout ; Microcystins/toxicity ; Mitosis/genetics ; Mitotic Index ; Phosphoprotein Phosphatases/antagonists & inhibitors ; RNA, Messenger/metabolism ; Tumor Suppressor Protein p53/deficiency ; Tumor Suppressor Protein p53/genetics
Chemical Substances	Bacterial Toxins ; Carcinogens ; Microcystins ; RNA, Messenger ; Tumor Suppressor Protein p53 ; Phosphoprotein Phosphatases (EC 3.1.3.16) ; cyanoginosin LR (EQ8332842Y)
Language	English
Publishing date	2008-02
Publishing country	United States
Document type	Comparative Study ; Journal Article
ZDB-ID	841009-4
ISSN	1533-1601 ; 0192-6233
ISSN (online)	1533-1601
ISSN	0192-6233
DOI	10.1177/0192623307311406
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Article: Identification and elucidation of the biology of adverse events: the challenges of safety assessment and translational medicine.

Turteltaub, Kenneth W / Davis, Myrtle A / Burns-Naas, Leigh Ann / Lawton, Michael P / Clark, Adam M / Reynolds, Jack A

Clinical cancer research : an official journal of the American Association for Cancer Research

2011 Volume 17, Issue 21, Page(s) 6641–6645

Abstract: There has been an explosion of technology-enabled scientific insight into the basic biology of the causes of adverse events. This has been driven, in part, by the development of the various "omics" tools (e.g., genomics, proteomics, and metabolomics) and ...

Abstract	There has been an explosion of technology-enabled scientific insight into the basic biology of the causes of adverse events. This has been driven, in part, by the development of the various "omics" tools (e.g., genomics, proteomics, and metabolomics) and associated bioinformatics platforms. Meanwhile, for decades, changes in preclinical testing protocols and guidelines have been limited. Preclinical safety testing currently relies heavily on the use of outdated animal models. Application of systems biology methods to evaluation of toxicities in oncology treatments can accelerate the introduction of safe, effective drugs. Systems biology adds insights regarding the causes and mechanisms of adverse effects, provides important and actionable information to help understand the risks and benefits to humans, focuses testing on methods that add value to the safety testing process, and leads to modifications of chemical entities to reduce liabilities during development. Leveraging emerging technologies, such as genomics and proteomics, may make preclinical safety testing more efficient and accurate and lead to better safety decisions. The development of a U.S. Food and Drug Administration guidance document on the use of systems biology in clinical testing would greatly benefit the development of drugs for oncology by communicating the potential application of specific methodologies, providing a framework for qualification and application of systems biology outcomes, and providing insight into the challenges and limitations of systems biology in the regulatory decision-making process.
MeSH term(s)	Animals ; Antineoplastic Agents/adverse effects ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Drug-Related Side Effects and Adverse Reactions/diagnosis ; Humans ; Systems Biology/methods ; Translational Medical Research
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2011-11-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-11-1106
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Article: Hepatic gene expression changes in mice associated with prolonged sublethal microcystin exposure.

Clark, Shawn P / Davis, Myrtle A / Ryan, Timothy P / Searfoss, George H / Hooser, Stephen B

Toxicologic pathology

2007 Volume 35, Issue 4, Page(s) 594–605

Abstract: Microcystin-LR (MCLR) is an acute hepatotoxicant and suspected carcinogen. Previous chronic studies have individually described hepatic morphologic changes, or alterations in the cytoskeleton, cell signaling or redox pathways. The objective of this study ...

Abstract	Microcystin-LR (MCLR) is an acute hepatotoxicant and suspected carcinogen. Previous chronic studies have individually described hepatic morphologic changes, or alterations in the cytoskeleton, cell signaling or redox pathways. The objective of this study was to characterize chronic effects of MCLR in wild-type mice utilizing gene array analysis, morphology, and plasma chemistries. MCLR was given daily for up to 28 days. RNA from the 28-day study was hybridized onto mouse genechip arrays. RNA from 4 hours, 24 hours, 4 days, 1 day, and 28 days for selected genes was processed for quantitative-PCR. Increases in plasma hepatic enzyme activities and decreases in total protein, albumin and glucose concentrations were identified in MCLR-treated groups at 14 and 28 days. Histologically, marked hepatokaryomegaly was identified in the 14-day MCLR group with the addition of giant cells at 28 days. Major gene transcript changes were identified in the actin organization, cell cycle, apoptotic, cellular redox, cell signaling, albumin metabolism, and glucose homeostasis pathways, and the organic anion transport polypeptide system. Using toxicogenomics, we have identified key molecular pathways involved in chronic sublethal MCLR exposure in wild-type mice, genes participating in those critical pathways and related them to cellular and morphologic alterations seen in this and other studies.
MeSH term(s)	Animals ; Blood Chemical Analysis ; Body Weight/drug effects ; Carcinogens/toxicity ; Chemical and Drug Induced Liver Injury/genetics ; Chemical and Drug Induced Liver Injury/pathology ; DNA, Complementary/biosynthesis ; DNA, Complementary/genetics ; Gene Expression/drug effects ; Genes, p53/genetics ; Genes, p53/physiology ; Liver/metabolism ; Liver/pathology ; Mice ; Mice, Knockout ; Microcystins/toxicity ; Oligonucleotide Array Sequence Analysis ; Organ Size/drug effects ; RNA/biosynthesis ; RNA/genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Toxicogenetics
Chemical Substances	Carcinogens ; DNA, Complementary ; Microcystins ; RNA (63231-63-0) ; cyanoginosin LR (EQ8332842Y)
Language	English
Publishing date	2007-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	841009-4
ISSN	0192-6233
ISSN	0192-6233
DOI	10.1080/01926230701383210
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