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Intramural Papers of the Month

By Robin Arnette
September 2008

Exposure to Lead May Prolong ALS Survival

Previous studies of lead suggested that the highly toxic metal was associated with increased risk of developing amyotrophic lateral sclerosis (ALS), but a team of scientists from NIEHS, Social and Scientific Systems, Inc., Westat and the University of Michigan reported that lead exposure was also associated with longer survival in ALS cases.

The authors said that given the small sample size and the unexpected results, the finding should be interpreted with caution. However, if the result is confirmed by other studies, it may contribute to understanding the mechanisms of disease progression and to developing therapies that prolong the lives of ALS sufferers.

The team measured levels of lead in blood and bone (in the tibia and patella) from 110 cases who participated in a case-control study conducted in New England in 1993–1996. The researchers found the strongest association with survival in patients who had high levels of lead in the tibia, although those with high blood and patella lead levels also had prolonged survival. Conversely, shorter survival was associated with older age at diagnosis, being female, decreased lung function, shorter interval between symptom onset and diagnosis, and bulbar onset of disease (difficulty in speech or swallowing).

Citation: Kamel F, Umbach DM, Stallone L, Richards M, Hu H, Sandler DP. ( NIEHS 2008. Association of lead exposure with survival in amyotrophic lateral sclerosis. Environ Health Perspect 116(7):943-947.

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The Involvement of RAP80 Following DNA Damage

NIEHS researchers showed that a mutant of the tumor suppressor breast cancer-1 (BRCA1), which is associated with an increased risk of breast cancer, was unable to both interact with RAP80 and translocate to ionizing radiation-induced foci (IRIF). Previous work had demonstrated that RAP80, a nuclear protein containing two ubiquitin-interacting motif (UIMs), was associated with BRCA1 and mediated the translocation of BRCA1 to IRIF following ionizing radiation (IR) and ultraviolet light (UV) treatment. Their experiments demonstrated that RAP80 is involved in several types of DNA damage responses.

Earlier research from the group had determined that ataxia-telangiectasia mutated (ATM) kinase phosphorylated a specific serine residue (Ser205) in RAP80 in vitro. To study this mechanism and its molecular implications in more detail, the team generated rabbit polyclonal antibody against phosphorylated Ser205 and used it to track RAP80 in MCF-7 cells treated with IR. The data indicated that phosphorylation occurred less than five minutes after radiation treatment and was independent of BRCA1. The team concluded ATM was responsible for the phosphorylation since RAP80 wasn’t phosphorylated when the same experiment was performed in A-T cells, a cell line that lacks ATM.

UV also induced phosphorylation of RAP80 at Ser205 and its translocation to DNA damage foci in response IR. This translocation event was dependent on the UIMs of RAP80 and RAD3-related kinase (ATR), an ATM-like kinase.

Citation: Yan J, Yang XP, Kim YS, Jetten AM. ( NIEHS 2008. RAP80 responds to DNA damage induced by both ionizing radiation and UV irradiation and is phosphorylated at Ser205. Cancer Res 68(11):4269-4276.

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Liver X Receptor Regulates Pulmonary Innate Immunity

The lung and the neutrophil are novel in vivo targets for pharmacologic Liver X Receptor (LXR) activation according to researchers at NIEHS and the National Jewish Medical and Research Center. The studies identify LXR stimulation as a potential tool for modulation of innate immunity in the lung.

The lungs, like the rest of the body, are exposed to potentially damaging agents, such as inflammatory environmental stimuli and bacterial infections. To fend off these attacks, the host organism’s immunological response, in particular the recruitment of polymorphonuclear neutrophils (PMNs) — white blood cells that kill microorganisms by engulfing them — must be precisely regulated. Since work from other labs found that the α and β forms of LXR, a nuclear receptor, were involved in proinflammatory gene expression, the team theorized that LXR regulated PMN recruitment to the lung when it was infected or inflamed.

To test this hypothesis, the researchers confirmed that LXR was expressed in the lung, and then treated mice with a synthetic LXR agonist prior to exposing their lungs to lipopolysaccharide (LPS), KC chemokine or the gram-negative bacterium Klebsiella pneumoniae. The team found that the LXR agonist attenuated PMN recruitment to the lungs and impaired pulmonary host defense.

Citation: Smoak K, Madenspacher J, Jeyaseelan S, Williams B, Dixon D, Poch KR, Nick JA, Worthen GS, Fessler MB. ( NIEHS 2008. Effects of liver X receptor agonist treatment on pulmonary inflammation and host defense. J Immunol 180(5):3305-3312.

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Differential Regulation of an ERK Protein Scaffold to Control Gene Transcription

Extracellular signal-regulated kinases 1 and 2 (ERKs 1and 2) differentially regulate transcriptional pathways by forming stable complexes with other proteins. Such a complex containing ERK1 was found to be present in neuronal nuclei and to respond differently to synaptic or depolarizing stimulation, whereas monomeric ERK1 responds equally well to both types of stimulation. The NIEHS researchers who report the finding believe that this protein scaffolding mechanism allows neuronal stimulation to regulate gene transcription differentially depending on whether the stimulation is normal or pathological.

Data indicated that because of its size, the large pERK-reactive complex (PERC-160) was restricted to the nuclei and contained phosphorylated ERK1 and 14-3-3 protein. Transglutaminase, a cross-linking enzyme that forms bonds between proteins, was proposed to make the structure extremely stable. Analysis using purified nuclei from rat forebrain demonstrated that ERK1 in the structure was dephosphorylated in response to potassium depolarization, representing abnormal neuronal activity, whereas it was phosphorylated in response to normal synaptic activity. The uncomplexed form of ERK was phosphorylated under both conditions.

The research represents the first evidence that neuronal complexed ERK may use different mechanisms to regulate gene transcription in response to various types of neuronal stimulation.

Citation: Lundquist JJ, Dudek SM. ( NIEHS 2008. Differential activation of extracellular signal-regulated kinase 1 and a related complex in neuronal nuclei. Brain Cell Biol 35(4-6):267-281.

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