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DERT Papers of the Month

By Jerry Phelps
June 2007

Inhibition of RelB Synthesis by ERα Signaling Controls the Shift in Breast Cancer Cell Phenotypes

RelB is a widely expressed protein involved in the regulation of genes involved in cell-to-cell interaction, intercellular communication, cell recruitment, spreading of pathogenic signals, cell apoptosis, and initiation or acceleration of tumorigenesis. RelB complexes are often found in mouse mammary tumors, but little is known about the function of RelB in relation to human breast cancer.

NIEHS grantee Gail Sonenshein at the Boston University School of Medicine reports in the April issue of Nature Cell Biology research findings that connect RelB with the estrogen receptor alpha (ERa). In invasive ERa-negative breast cancer cells, her team found active synthesis of RelB; however, ERα signaling led to an inhibition of RelB synthesis, leading to an inverse correlation between RelB and ERa gene expression in human breast cancer tissues and cell lines. Additional studies demonstrated that RelB promotes a more invasive type of ERa-negative breast cancer cells.

This work provides further understanding of the role of RelB in human breast cancer and indicates that inhibition of RelB synthesis represents a mechanism by which ERα can control the shift of epithelial cells to a more invasive phenotype. The authors conclude that further studies are warranted to determine if RelB is useful as a marker or in therapeutic approaches for the detection and treatment of metastatic breast cancer.

Citation: Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F, Chalbos D, Sonenshein GE(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=17369819&query_hl=2&itool=pubmed_docsum Exit NIEHS. 2007. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol 9(4):470-478.

Riboflavin Activated by UV Exposure Causes Oxidative DNA Damage, Which Is Inhibited by Vitamin C

NIEHS grantee Gerd Pfeifer and colleagues at the Beckman Research Institute report intriguing results of experiments involving the essential vitamin riboflavin. They found that riboflavin causes oxidative DNA damage when it is activated by ultraviolet radiation in a mouse fibroblast cell culture model. These effects were blocked when vitamin C was co-administered.

Pfeifer is one of only nine current Method to Extend Research In Time (MERIT) grantees at NIEHS. This is a prestigious award given only to very highly productive researchers who are leaders in their respective fields and have a history of good grantsmanship.

This work expands on a popular theory that wavelengths of light in the ultraviolet A (UVA) range trigger intracellular photosensitization reactions, leading to promutagenic oxidative DNA damage. Riboflavin, also known as vitamin B2, is known to be a cellular photosensitizer and was shown in the current studies to intensify the UVA-induced damage. However, vitamin C at a physiologic relevant dose exerted antioxidant effects and protected the cells from oxidative DNA damage. These findings confirm that UVA induced-genotoxicity is caused by intracellular photosensitization reactions, which generate oxidative and promutagenic damage to DNA.

Citation: Besaratinia A, Kim SI, Bates SE, Pfeifer GP(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=17389394&query_hl=5&itool=pubmed_docsum Exit NIEHS. 2007. Riboflavin activated by ultraviolet A1 irradiation induces oxidative DNA damage-mediated mutations inhibited by vitamin C. Proc Natl Acad Sci U S A 104(14):5953-5958.

Autism Disorder Risk Increased in Babies of Mothers with Glutathione S-Transferase P1 Haplotype

Grantees from the NIEHS-supported Center for Childhood Neurotoxicology and Exposure Assessment at the University of Medicine and Dentistry of New Jersey have found a positive correlation between a diagnosis of autism in children and a polymorphism in a gene coding for the enzyme glutathione S-transferase (GST) in their mothers. This finding suggests that autism may be the result of a gene-environment interaction and suggests a possible mechanism for the design of strategies for prevention and treatment.

The researchers determined the frequency of glutathione polymorphisms in 137 members of 49 families with histories of autism disorder. Autism was confirmed using two common diagnostic screening methods. They found that the autism case mothers were 2.7 times more likely to carry the GSTP1*A haplotype. GSTs are active in the detoxification of endogenous compounds such as peroxidized lipids as well as the metabolism of xenobiotics.

If confirmed by additional studies, this finding represents a major step in determining whether autism disorders are the result of gene-environment interactions. It also raises questions as to whether the effect is the result of conjugation of glutathione with toxins. These results may provide insight into the toxins that might cause the effect and could lead to the therapeutic or preventive strategies for autism disorders.

Citation: Williams TA, Mars AE, Buyske SG, Stenroos ES, Wang R, Factura-Santiago MF, Lambert GH, Johnson WG(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=17404132&query_hl=7&itool=pubmed_docsum Exit NIEHS. 2007. Risk of autistic disorder in affected offspring of mothers with a glutathione S-transferase P1 haplotype. Arch Pediatr Adolesc Med 161(4):356-361.

Radiation-Induced Male Sterility Is due to Damage in the Somatic Testicular Cells and not the Spermatogonia

Researchers at the University of Texas M.D. Anderson Cancer Center have discovered that male sterility caused by exposure to radiation, such as that experienced during cancer treatment, is due to damage to the somatic cells within the testis - and not, as widely believed, a direct effect of damage to the spermatogonial stem cells.

The investigative team used laboratory rats and mice to conduct their experiments; however, they are confident that the results will hold true for humans. They transplanted populations of rat testicular cells containing stem spermatogonia that express green fluorescent protein into a variety of host animals. Transplantation into irradiated rat testes showed that the stem cells were able to colonize their new surroundings, but were not able to develop and grow - a process called differentiation.

With the advances in cancer therapy leading to longer survival, quality of life issues especially in children and young adults are increasingly important. Autologous transplantation of preserved spermatogonia is being investigated as a potential method to regenerate spermatogenesis in former cancer patients treated with chemotherapy or radiation. These findings suggest that transplanted spermatogonial stem cells may not be able to differentiate due to damage to other testicular cells and further suggest that additional treatments focusing on the somatic environment may be necessary.

Citation: Zhang Z, Shao S, Meistrich ML(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=Abstract&list_uids=17167785&query_hl=10&itool=pubmed_docsum Exit NIEHS. 2007. The radiation-induced block in spermatogonial differentiation is due to damage to the somatic environment, not the germ cells. J Cell Physiol 211(1):149-158.



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