Analysis of dose-response to hexanal-induced gene expression in A549 human alveolar cells

2014 ◽  
Vol 8 (2) ◽  
pp. 75-82 ◽  
Author(s):  
Yoon Cho ◽  
Mi-Kyung Song ◽  
Han-Seam Choi ◽  
Jae-Chun Ryu
Keyword(s):  
Gene Expression ◽  
Dose Response ◽  
Alveolar Cells

scholarly journals Nonmonotonic Pathway Gene Expression Analysis Reveals Oncogenic Role of p27/Kip1 at Intermediate Dose

2017 ◽  
Vol 16 ◽  
pp. 117693511774013 ◽  
Author(s):  
Hien H Nguyen ◽  
Susan C Tilton ◽  
Christopher J Kemp ◽  
Mingzhou Song
Keyword(s):  
Gene Expression ◽  
Pathway Analysis ◽  
Dose Response ◽  
Response Analysis ◽  
Response Curves ◽  
Cancer Pathways ◽  
Pathway Gene ◽  
Mechanistic Basis ◽  
Functional Pathway ◽  
Squamous Cell Papilloma

The mechanistic basis by which the level of p27Kip1 expression influences tumor aggressiveness and patient mortality remains unclear. To elucidate the competing tumor-suppressing and oncogenic effects of p27Kip1 on gene expression in tumors, we analyzed the transcriptomes of squamous cell papilloma derived from Cdkn1b nullizygous, heterozygous, and wild-type mice. We developed a novel functional pathway analysis method capable of testing directional and nonmonotonic dose response. This analysis can reveal potential causal relationships that might have been missed by other nondirectional pathway analysis methods. Applying this method to capture dose-response curves in papilloma gene expression data, we show that several known cancer pathways are dominated by low-high-low gene expression responses to increasing p27 gene doses. The oncogene cyclin D1, whose expression is elevated at an intermediate p27 dose, is the most responsive gene shared by these cancer pathways. Therefore, intermediate levels of p27 may promote cellular processes favoring tumorigenesis—strikingly consistent with the dominance of heterozygous mutations in CDKN1B seen in human cancers. Our findings shed new light on regulatory mechanisms for both pro- and anti-tumorigenic roles of p27Kip1. Functional pathway dose-response analysis provides a unique opportunity to uncover nonmonotonic patterns in biological systems.

Testing for Trends in Dose-Response Microarray Experiments: A Comparison of Several Testing Procedures, Multiplicity and Resampling-Based Inference

2007 ◽  
Vol 6 (1) ◽  
Author(s):  
Dan Lin ◽  
Ziv Shkedy ◽  
Dani Yekutieli ◽  
Tomasz Burzykowski ◽  
Hinrich W.H. Göhlmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dose Response ◽  
Multiple Testing ◽  
Pharmaceutical Research ◽  
Ratio Test ◽  
Familywise Error Rate ◽  
Response Level ◽  
Data Set ◽  
Monotonic Trend ◽  
Testing Procedures

Dose-response studies are commonly used in experiments in pharmaceutical research in order to investigate the dependence of the response on dose, i.e., a trend of the response level toxicity with respect to dose. In this paper we focus on dose-response experiments within a microarray setting in which several microarrays are available for a sequence of increasing dose levels. A gene is called differentially expressed if there is a monotonic trend (with respect to dose) in the gene expression. We review several testing procedures which can be used in order to test equality among the gene expression means against ordered alternatives with respect to dose, namely Williams' (Williams 1971 and 1972), Marcus' (Marcus 1976), global likelihood ratio test (Bartholomew 1961, Barlow et al. 1972, and Robertson et al. 1988), and M (Hu et al. 2005) statistics. Additionally we introduce a modification to the standard error of the M statistic. We compare the performance of these five test statistics. Moreover, we discuss the issue of one-sided versus two-sided testing procedures. False Discovery Rate (Benjamni and Hochberg 1995, Ge et al. 2003), and resampling-based Familywise Error Rate (Westfall and Young 1993) are used to handle the multiple testing issue. The methods above are applied to a data set with 4 doses (3 arrays per dose) and 16,998 genes. Results on the number of significant genes from each statistic are discussed. A simulation study is conducted to investigate the power of each statistic. A R library IsoGene implementing the methods is available from the first author.

Sex-dependent dose response of gene expression modulation after ochratoxin A insult in F344 rats

2017 ◽  
Vol 280 ◽  
pp. S88
Author(s):  
Ariane Vettorazzi ◽  
Laura Pastor ◽  
Adela López de Cerain
Keyword(s):  
Gene Expression ◽  
Ochratoxin A ◽  
Dose Response ◽  
Expression Modulation ◽  
F344 Rats

Nuclear targeting of stanniocalcin to mammary gland alveolar cells during pregnancy and lactation

2005 ◽  
Vol 289 (4) ◽  
pp. E634-E642 ◽  
Author(s):  
Craig P. Hasilo ◽  
Christopher R. McCudden ◽  
J. Ryan J. Gillespie ◽  
Kathi A. James ◽  
Edward R. Hirvi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mammary Gland ◽  
Molecular Mass ◽  
Chemical Reduction ◽  
Mammary Tissue ◽  
Nuclear Targeting ◽  
Alveolar Cells ◽  
Hormone Production ◽  
Pregnant Rats ◽  
Pregnancy And Lactation

In most mammalian tissues, the stanniocalcin-1 gene (STC-1) produces a 50-kDa polypeptide hormone known as STC50. Within the ovaries, however, the STC-1 gene generates three higher-molecular-mass variants known as big STC. Big STC is targeted locally to corpus luteal cells to block progesterone release. During pregnancy and lactation, however, ovarian big STC production increases markedly, and the hormone is released into the serum. During lactation, this increase in hormone production is dependent on a suckling stimulus, suggesting that ovarian big STC may have regulatory effects on the lactating mammary gland. In this report, we have addressed this possibility. Our results revealed that virgin mammary tissue contained large numbers of membrane- and mitochondrial-associated STC receptors. However, as pregnancy progressed into lactation, there was a decline in receptor densities on both organelles and a corresponding rise in nuclear receptor density, most of which were on milk-producing, alveolar cells. This was accompanied by nuclear sequestration of the ligand. Sequestered STC resolved as one ∼135-kDa band in the native state and therefore had the appearance of a big STC variant. However, chemical reduction collapsed this one band into six closely spaced, lower-molecular-mass species (28–41 kDa). Mammary gland STC production also underwent a dramatic shift during pregnancy and lactation. High levels of STC gene expression were observed in mammary tissue from virgin and pregnant rats. However, gene expression then fell to nearly undetectable levels during lactation, coinciding with the rise in nuclear targeting. These findings have thus shown that the mammary glands are indeed targeted by STC, even in the virgin state. They have further shown that there are marked changes in this targeting pathway during pregnancy and lactation, accompanied by a switch in ligand source (endogenous to exogenous). They also represent the first example of nuclear targeting by STC.

scholarly journals Repeat Transduction in the Mouse Lung by Using Adeno-Associated Virus Vectors with Different Serotypes

2000 ◽  
Vol 74 (3) ◽  
pp. 1524-1532 ◽  
Author(s):  
Christine L. Halbert ◽  
Elizabeth A. Rutledge ◽  
James M. Allen ◽  
David W. Russell ◽  
A. Dusty Miller
Keyword(s):  
Gene Expression ◽  
Neutralizing Antibodies ◽  
Mouse Lung ◽  
Airway Epithelial ◽  
Alveolar Cells ◽  
Adeno Associated Virus ◽  
Primary Vector ◽  
Prior Administration ◽  
Vector Transduction

ABSTRACT Vectors derived from adeno-associated virus type 2 (AAV2) promote gene transfer and expression in the lung; however, we have found that while gene expression can persist for at least 8 months in mice, it was reduced dramatically in rabbits over a period of 2 months. The efficiency and persistence of AAV2-mediated gene expression in the human lung have yet to be determined, but it seems likely that readministration will be necessary over the lifetime of an individual. Unfortunately, we have found that transduction by a second administration of an AAV2 vector is blocked, presumably due to neutralizing antibodies generated in response to the primary vector exposure. Here, we have explored the use of AAV2 vectors pseudotyped with capsid proteins from AAV serotypes 2, 3, and 6 for readministration in the mouse lung. We found that an AAV6 vector transduced airway epithelial and alveolar cells in the lung at rates that were at least as high as those of AAV2 pseudotype vectors, while transduction rates mediated by AAV3 were much lower. AAV6 pseudotype vector transduction was unaffected by prior administration of an AAV2 or AAV3 vector, and transduction by an AAV2 pseudotype vector was unaffected by prior AAV6 vector administration, showing that cross-reactive neutralizing antibodies against AAV2 and AAV6 are not generated in mice. Interestingly, while prior administration of an AAV2 vector completely blocked transduction by a second AAV2 pseudotype vector, prior administration of an AAV6 vector only partially inhibited transduction by a second administration of an AAV6 pseudotype vector. Analysis of sera obtained from mice and humans showed that AAV6 is less immunogenic than AAV2, which helps explain this finding. These results support the development of AAV6 vectors for lung gene therapy both alone and in combination with AAV2 vectors.

scholarly journals Negative autoregulation linearizes the dose-response and suppresses the heterogeneity of gene expression

2009 ◽  
Vol 106 (13) ◽  
pp. 5123-5128 ◽  
Author(s):  
D. Nevozhay ◽  
R. M. Adams ◽  
K. F. Murphy ◽  
K. Josic ◽  
G. Balazsi
Keyword(s):  
Gene Expression ◽  
Dose Response ◽  
Negative Autoregulation

scholarly journals Non-monotonic dose–response relationship in steroid hormone receptor-mediated gene expression

2007 ◽  
Vol 38 (5) ◽  
pp. 569-585 ◽  
Author(s):  
Li Li ◽  
Melvin E Andersen ◽  
Steffen Heber ◽  
Qiang Zhang
Keyword(s):  
Gene Expression ◽  
Dose Response ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Nonlinear Process ◽  
Steroid Hormone Receptors ◽  
Transcription Activator ◽  
Synthetic Drugs ◽  
Exogenous Ligand ◽  
Response Behaviors

Steroid hormone receptors are the targets of many environmental endocrine active chemicals (EACs) and synthetic drugs used in hormone therapy. While most of these chemical compounds have a unidirectional and monotonic effect, certain EACs can display non-monotonic dose–response behaviors and some synthetic drugs are selective endocrine modulators. Mechanisms underlying these complex endocrine behaviors have not been fully understood. By formulating an ordinary differential equation-based computational model, we investigated in this study the steady-state dose–response behavior of exogenous steroid ligands in an endogenous hormonal background under various parameter conditions. Our simulation revealed that non-monotonic dose–responses in gene expression can arise within the classical genomic framework of steroid signaling. Specifically, when the exogenous ligand is an agonist, a U-shaped dose–response appears as a result of the inherently nonlinear process of receptor homodimerization. This U-shaped dose–response curve can be further modulated by mixed-ligand heterodimers formed between endogenous ligand-bound and exogenous ligand-bound receptor monomers. When the heterodimer is transcriptionally inactive or repressive, the magnitude of U-shape increases; conversely, when the heterodimer is transcriptionally active, the magnitude of U-shape decreases. Additionally, we found that an inverted U-shaped dose–response can arise when the heterodimer is a strong transcription activator regardless of whether the exogenous ligand is an agonist or antagonist. Our work provides a novel mechanism for non-monotonic, particularly U-shaped, dose–response behaviors observed with certain steroid mimics, and may help not only understand how selective steroid receptor modulators work but also improve risk assessment for EACs.

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