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May 2011

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Intramural papers of the month

By Mamta Behl, Archana Dhasarathy, and Angelika Zaremba
May 2011

Physiological key player found for glucose-induced insulin secretion

NIEHS researchers, in collaboration with scientists from the University of California, Los Angeles David Geffen School of Medicine, have identified the G(o2) protein as a physiological key player in the control of glucose-induced insulin secretion by pancreatic beta cells. The finding may lead to better treatments for diabetic patients managing their insulin levels.

Insulin secretion by pancreatic beta cells is highly regulated, with G proteins controlling the output of insulin in response to physiological demands. Any malfunction in the system can lead to diabetes mellitus. Bordetella pertussin toxin (PTX) has been known to stimulate insulin release from pancreatic beta cells for nearly 30 years. However, the exact molecular target of PTX has not been identified. There are five different nonsensory G(i) or G(o) proteins upon which PTX could act to stimulate insulin release. These proteins displayed extensive homology and are functionally similar. Members of the research team used mouse model knockouts and determined that G(o2) was the target G protein responsible for the increased insulin release after PTX treatment.

The components in G protein signaling pathways and their downstream effectors have been a rich source of targets for pharmaceuticals. Identifying key players in this complex process will direct future investigations to improve the treatment of abnormal insulin secretion such as in diabetes mellitus.

Citation: Wang Y, Park S, Bajpayee NS, Nagaoka Y, Boulay G, Birnbaumer L, Jiang M.( Exit NIEHS 2011. Augmented glucose-induced insulin release in mice lacking G(o2), but not G(o1) or G(i) proteins. Proc Natl Acad Sci U S A 108(4):1693-1698.

Dioxin targets the blood-brain barrier

Environmental toxicants, such as dioxins, have long been known to affect the liver, but new research from NIEHS suggests these chemicals may act through the aryl hydrocarbon receptor (AhR) to alter the way that the blood-brain barrier handles therapeutic drugs. One such toxicant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), increased the production of P-glycoprotein in rat brain capillaries. P-glycoprotein is an ATP-driven drug efflux pump that functions as a gate-keeper for the brain, limiting entry of both neurotoxicants and therapeutic drugs.

The researchers found that in addition to increasing P-glycoprotein expression, TCDD increased the transport activity of two other efflux pumps - multidrug resistance-associated protein 2 and breast cancer resistance polypeptide. The study also demonstrated that TCDD increased expression of two classical AhR target genes, Cyp1a1 and Cyp1b1, which code for enzymes that metabolize certain foreign chemicals.

Finally, the authors demonstrated that in TCDD-dosed rats, brain accumulation of the drug and P-glycoprotein substrate verapamil, was reduced. This work provides a mechanism by which dioxins may reduce the ability of drugs to enter the central nervous system, thus making it more difficult to treat disease.

Citation: Wang X, Hawkins BT, Miller DS.( Exit NIEHS 2011. Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. FASEB J 25(2):644-652.

Comparison of global gene expression profiles in response to xenoestrogens

NIEHS investigators have  published a study comparing the activity and responses of two xenoestrogenic compounds, bisphenol A (BPA) and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE). The research will help other scientists assess patterns of response and molecular mechanisms of potentially estrogenic chemicals.

Since BPA and HPTE are known to interact with estrogen receptor alpha (ERalpha), an important nuclear receptor that modulates estrogen-dependent gene expression, the authors developed a mouse uterine model system to study the direct targets of estrogenic compounds. They used microarray gene expression profiling to compare uterine responses following the addition of estrogens E2 or E3, BPA, or HPTE, for 2 or 24 hours. Both BPA and HPTE induced cell proliferation, but not to the same extent as estrogen.

When compared to E2, BPA and HPTE were able to elicit early, but not late stage gene expression changes, a pattern similar to the weak estrogen E3. In addition, using mice carrying a DNA-binding mutant of ERalpha, the authors show that the "tethered response mechanism" of estrogen receptor is sensitive to xenoestrogens, as BPA and HPTE elicited the same responses as E2.

BPA is widely used in plastics, and HPTE is a metabolite of the pesticide methoxychlor, thus raising concerns over their negative impact on human health. This study provides a useful model to test potential estrogenicity and mode of response of other xenoestrogenic compounds.

Citation: Hewitt SC, Korach KS.( Exit NIEHS 2011. Estrogenic activity of bisphenol A and 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE) demonstrated in mouse uterine gene profiles. Environ Health Perspect 119(1):63-70.

Study highlights importance of protein complexes in liver metabolism

Researchers from NIEHS found that the Med25 protein was important in helping hepatocyte nuclear factor 4alpha (HNF4alpha) direct gene expression. HNF4alpha is a nuclear receptor that functions in regulating gene expression in the liver, kidney, pancreas, and intestines. This report is the first to identify Med25, a variable member of the mediator complex, as a new coactivator for HNF4alpha.

Using various biochemical approaches, the authors detected Med25 as an HNF4alpha interacting protein. They showed that Med25 helped HNF4alpha activate certain genes by converting the HNF4alpha bound transcriptional complex from the inactive to the active state, facilitating the recruitment of RNA polymerase II to the promoter site. At the molecular level, Med25 increases the association of HNF4alpha with proteins that help activate genes, such as the Mediator complex, coactivators, and RNA polymerase II. The authors also showed that Med25 interaction with HNF4alpha gives HNF4alpha an exquisite specificity in controlling those genes that are responsible for lipid and drug metabolism in human liver cells.

Mutations of HNF4alpha have been linked to diabetes, liver metabolic diseases, and impaired drug metabolism. This study highlights one cofactor, Med25, which confers selectivity in targeting HNF4alpha activation of distinct gene targets.

Citation: Rana R, Surapureddi S, Kam W, Ferguson S, Goldstein JA. ( Exit NIEHS 2011. Med 25 is required for RNA polymerase II recruitment to specific promoters, thus regulating xenobiotic and lipid metabolism in human liver. Mol Cell Biol 31(3):466-481.

(Mamta Behl, Ph.D., is a research fellow in the NIEHS Toxicology Branch. Archana Dhasarathy, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Carcinogenesis Eukaryotic Transcriptional Regulation Group. Angelika Zaremba, Ph.D., is a visiting fellow in the NIEHS Laboratory of Signal Transduction Inositol Signaling Group.)

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