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Intramural Papers of the Month

By Robin Arnette
June 2008

Indicators of Obesity Are Related to Disability in the Elderly

The indicators of obesity, such as body mass index (BMI) and waist circumference, are related to functional disabilities in elderly Americans, according to a study published by NIEHS researchers. The data was compiled using the National Health and Nutrition Examination Survey (NHANES 1999-2004) and represents a key finding in disability prevention and intervention for this population.

The NHANES surveyed 1,684 women and 1,611 men aged 60 years and older and determined whether they had difficulty with activities of daily living, instrumental activities of daily living, leisure and social activities, lower extremity mobility and general physical activity. The team determined that those with higher BMI or waist circumference were more likely to experience functional disabilities. Waist circumference appeared to be a better indicator of disability in elderly women than BMI; the pattern for elderly men was less evident.

The study authors acknowledged that obese individuals tend to suffer from chronic illnesses such as diabetes, cardiovascular and pulmonary diseases, and certain cancers, and that these conditions may increase the risk of developing functional disabilities. However, the presence of these infirmities in some of the survey participants did not explain the results of the research. Because the study's large sample size included a variety of different ethnic groups and social classes, the conclusions apply to the overall population of elderly Americans.

Citation: Chen H, Guo X.( Exit NIEHS Website 2008. Obesity and functional disability in elderly Americans. J Am Geriatr Soc 56(4):689-694.

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Altered RNA-binding in Yeast Puf4p

X-ray crystallographic analysis has determined how yeast Puf4p uses its 8 nucleotide (nt) binding sites, in the form of 8 ?-helical repeats, to bind a 9-nt target RNA sequence. NIEHS researchers used minor structural modifications to create a mutant Puf4p that preferentially binds 8-nt, one RNA base per repeat. The finding will lead to a greater understanding of translational regulation.

Puf4p is a member of the Pumilio/FBF (PUF) family of proteins, and like other members of this family, it regulates eukaryotic gene expression post-transcriptionally by binding target RNA. This action is vital for stem cell maintenance and embryonic development in animals and other regulatory processes in plants and yeast.

The prototypical PUF protein Pumilio uses its 8 ?-helical repeats to bind the 8-nt RNA sequence UGUA-U/C-AUA, but Puf4p binds 9-nt, while Puf5p - also known as Mpt5p - binds 10-nt. The NIEHS team crystallized Puf4p alone and with its 9-nt sequence (UGUAUAUUA) to determine how the additional nucleotide is accommodated.

The results indicated that the fifth (U5) and seventh (U7) nucleotides in the RNA sequence didn't directly interact with Puf4p and the seventh nucleotide protrudes from the RNA-binding surface. The team mutated residues responsible for RNA recognition in PUF proteins that bind to 8-nt sequences and generated a Puf4p that preferentially bound the 8-nt RNA target sequence.

Citation: Miller MT, Higgin JJ, Tanaka Hall TM.( Exit NIEHS Website 2008. Basis of altered RNA-binding specificity by PUF proteins revealed by crystal structures of yeast Puf4p. Nature Struct Mol Biol 15(4):397-402.

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Glis2 is Critical for Proper Kidney Function

Researchers at NIEHS demonstrated that Gli-similar 2 (Glis2), a member of a subfamily of Krüppel-like zinc finger proteins, is critical for the maintenance of normal renal architecture and function.

To obtain insights into the physiological functions of Glis2, the investigators generated mutant mice that lacked Glis2 (Glis2mut) and compared the phenotype with that of wild-type (WT) mice. The team found that Glis2mut mice developed chronic kidney disease that resembled nephronophthisis, an autosomal recessive disease that is characterized by progressive tubular atrophy, severe interstitial fibrosis, infiltration of inflammatory cells, glomerulosclerosis and scarring of the kidney's blood vessels. These symptoms ultimately led to premature renal failure. Nephronophthisis is the most frequent genetic cause for end-stage renal failure in humans and recent work from another lab linked mutations in the GLIS2 gene to nephronophthisis in humans.

Comparison of gene expression profiles of WT and Glis2mut renal cells demonstrated that expression of a number of genes involved in inflammation and tissue remodeling and that the epithelial-mesenchymal transition is altered in kidneys of Glis2mut mice. Thus, the Glis2mut mice will provide an excellent model to study the molecular events that play a role in the initiation and progression of nephronophthisis and renal failure.

Citation:Kim YS, Kang HS, Herbert R, Beak JY, Collins JB, Grissom SF, Jetten AM.( Exit NIEHS Website 2008. Krüppel-like zinc finger protein Glis2 is essential for the maintenance of normal renal functions. Mol Cell Biol 28(7):2358-2367.

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Vitamin E and NAG-1 Play a Role in Prostate Cancer

Vitamin E succinate (VES), the succinate derivative of ?-tocopherol, induces expression of the nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) in PC-3 human prostate carcinoma cells. This process occurs in a p38 kinase-dependent manner and leads to growth arrest and apoptosis in the cell line. The NIEHS researchers who published the findings believe the results point to NAG-1 as a possible therapeutic target in prostate cancer.

The team determined that prostate carcinoma cells that underwent VES treatment produced a time- and concentration-dependent increase in NAG-1 protein levels and eventually led to apoptosis. VES treatment also led to the activation and transfer of p38 into the nucleus, but pre-treating the cells with a p38 kinase inhibitor blocked an increase in NAG-1. Similarly, the expression of MMK6, an upstream kinase of p38, induced an increase in NAG-1 promoter activity, while the p38 inhibitor blocked NAG-1 promoter activity.

Data from transfection and small interfering RNA (siRNA) experiments explained the mechanism behind the VES and NAG-1 interaction. VES stabilized NAG-1 mRNA transcripts through NAG-1's AU-rich segments in its 3'-untranslated region and siRNA for NAG-1 blocked VES-induced poly(ADP-ribose) polymerase cleavage. Taken together these results suggested that NAG-1 along with p38 could play a chemopreventive role in prostate cancer.

Citation: Shim M, Eling TE.( Exit NIEHS Website 2008. Vitamin E succinate induces NAG-1 expression in a p38 kinase-dependent mechanism. Mol Cancer Ther 7(4):961-971.

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