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Environmental Factor

November 2011

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Intramural papers of the month

By Raluca Dumitru, Brant Hamel, Sonika Patial, and Sheetal Thakur
November 2011

Two point mutations may influence the efficacy of breast cancer treatment

A new study by NIEHS researchers reveals that mutating two amino acids, L543 and L544, in the helix 12 of the AF-2 region of estrogen receptor alpha (ERalpha) reduces estradiol-induced gene transcription and also converts selective ER modulators (SERMs) such as Tamoxifen (TAM) or the ER antagonist ICI182780 (ICI) from antagonists into agonists. The findings in an innovative knock-in mouse model and in vitro data offer new insights into the tissue-selective functions of SERMs, drugs which are widely used to prevent and treat breast cancer by interfering with the activity of estrogen. Significantly, the paper is the first report showing that estrogen does not activate the function of AF-1 independent of AF-2 and that certain tissues have a preference for AF-1 versus AF-2 activities.

ERalpha belongs to the nuclear receptor subfamily of ligand-inducible transcription factors. This ligand-induced transcription of ERalpha involves the action of two distinct activation functions, AF-1 and AF-2, which are located in the N-terminal and C-terminal regions, respectively. AF-1 and AF-2 can act interdependently or in concert with each other, as suggested by previous in vitro cell studies.

The researchers demonstrated that a functional AF-2 is absolutely critical for regulating some female reproductive-tissue hormone responses, but other tissues utilize the AF-1 functionality. Along with their mouse experiments, researchers used in vitro assays to show that ICI activates AF-2 mutated ERĪ± predominantly through the AF-1 region in different tumor tissue cell types.

Citation: Arao Y, Hamilton KJ, Ray MK, Scott G, Mishina Y, Korach KS ( Exit NIEHS. 2011. Estrogen receptor alpha AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators. Proc Natl Acad Sci USA 108(36):14986-14991.

IL-35 production by regulatory T cells reverses allergic asthma

A new study from investigators at NIEHS implicates a recently discovered cytokine, IL-35, as critical for regulating allergic responses in the airway. IL-35 was found to be produced specifically in inducible costimulator (ICOS)-positive regulatory T cells and to prevent airway hyperresponsiveness (AHR), a key clinical symptom of allergic asthma. This work suggests that targeting the IL-35 pathway may benefit patients who suffer from AHR.

The researchers found that in allergen-sensitized mice, a single subsequent allergen initially caused AHR, but that repeated exposures quickly led to down-regulation of that response. Building upon previous work in the lab, decreasing levels of IL-17 were shown to contribute to the loss of AHR. The authors went on to demonstrate that rising numbers of ICOS+ Treg cells led to a decrease in IL-17 levels through a mechanism dependent on the presence of ICOS and its ligand, B7h, as well as the production of IL-35 by these cells. This study suggests that pharmacological mechanisms that boost IL-35 production may prove beneficial in the treatment of allergic asthma by decreasing IL-17 levels and AHR.

Citation: Whitehead GS, Wilson RH, Nakano K, Burch LH, Nakano H, Cook DN( Exit NIEHS. 2011. IL-35 production by inducible costimulator (ICOS)-positive regulatory T cells reverses established IL-17-dependent allergic airways disease. J Allergy Clin Immunol; doi:10.1016/j.jaci.2011.08.009 [Online 7 September 2011].

New rank-based methodology useful for large-scale association studies

NIEHS biostatisticians have developed a novel approach that can be used for allotting the proper sample size in genomic association studies and for determining the number of initial results to follow up on after completion of a study. The approach is based on the evaluation of probability that genuine discoveries will have a specific rank in a list of results sorted by their P-values. This rank-based approach is well suited for studies with different marker densities and linkage disequilibrium patterns and applicable any time a large number of statistical tests are conducted simultaneously.

The researchers wanted a way to analyze top hits, selected from the large number of susceptibility gene variants generated by a study. The rank-based process that they developed for that purpose utilizes a mathematical model to ensure accurate selection of top hits based on controlling the proportion of genuine discoveries among them.

In conjunction with the development of their rank-based analysis, the authors developed software that allows scientists to estimate ranking probabilities and the number of top hits that would contain true associations with a specified probability. The software allows researchers to plan discovery and replication stages in large-scale genomic studies.

Citation: Kuo CL, Zaykin DV ( Exit NIEHS. 2011. Novel rank-based approaches for discovery and replication in genome-wide association studies. Genetics 189(1):329-340.

Heat-Shock Protein 70 is an important regulator of O3-induced lung inflammation

A new collaborative study between researchers from NIEHS, Michigan State University, and Johns Hopkins University has identified heat shock proteins that act as effector molecules in response to ozone (O3)-induced toll-like receptor 4 (Tlr4) signaling. This group found Tlr4 to be involved in O3-induced pulmonary inflammation, but the downstream signaling events were unknown until the research team determined the mechanism.

Tlr4 protein is activated by the binding of ligands, which leads to the recruitment of adaptor molecules such as MyD88. Tlr4 mutant and Tlr4 normal mice were exposed to O3 and to filtered air as a control. In response to O3, Tlr4 signaling significantly upregulated MyD88-dependent and independent pathways in Tlr4 normal mice, but not Tlr4 mutant mice, suggesting that both effector pathways were involved in mediating O3-induced inflammation and hyperpermeability.

Microarray analysis further identified heat-shock proteins as one of the groups of proteins significantly upregulated in Tlr4 normal mice relative to Tlr4 mutants. Hsp70 knockout mice displayed a lower degree of inflammation and hyperpermeability compared with wild-type mice, thus validating the importance of Hsp70 in response to O3.

The results of this study demonstrate that heat shock proteins are effectors in response to O3-induced TLR4 signaling and these novel findings may have therapeutic and preventive implications for inflammatory diseases resulting from environmental exposures.

Citation: Bauer AK, Rondini EA, Hummel KA, Degraff LM, Walker C, Jedlicka AE, Kleeberger SR ( Exit NIEHS. 2011. Identification of candidate genes downstream of TLR4 signaling after ozone exposure in mice: a role for heat shock protein 70. Environ Health Perspect 119(8):1091-1097.

(Raluca Dumitru, M.D., Ph.D., is an Intramural Research Training Award fellow in the NIEHS Stem Cell Biology Group of the Laboratory of Molecular Carcinogenesis. Brant Hamel Ph.D., is an Intramural Research Training Award fellow in the NIEHS Molecular Endocrinology Group of the Laboratory of Signal Transduction. Sonika Patial, Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction. Sheetal Thakur, Ph.D., is a visiting fellow in the NIEHS NTP Toxicology Branch.)

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