1: Allergy. 2005 Jun;60(6):760-5. 

Polymorphism of tandem repeat in promoter of 5-lipoxygenase in ASA-intolerant
asthma: a positive association with airway hyperresponsiveness.

Kim SH, Bae JS, Suh CH, Nahm DH, Holloway JW, Park HS.

Department of Allergy and Rheumatology, Ajou University School of Medicine,
Suwon, Korea.

BACKGROUND: 5-Lipooxygenase (ALOX5) and 5-lipoxygenase-activating protein
(ALOX5AP) are known as key enzymes in cysteinyl-leukotriene (cys-LT) production,
critical mediators in aspirin acetylsalicyclic acid (ASA)-intolerant asthma
(AIA). To date, studies of the promoter region of ALOX5 gene has revealed the
potential influence of a variable number of tandem repeats of a Sp1- and
Egr1-binding motif, on the transcription rate. METHODS: To understand the
pathological process that arises from cys-LT overproduction in AIA, we genotyped
ALOX5 Sp1 and ALOX5AP poly(A) repeat promoter polymorphism by fluorescent-based
capillary electrophoresis in the Korean population. RESULTS: No significant
differences in allele and genotype frequencies of the ALOX5 and ALOX5AP promoter
polymorphisms were observed between the three groups. However, there was a
strong association of the ALOX5 Sp1 repeat polymorphism with airway
hyperresponsiveness (AHR; PC20 methacholine); AIA patients carrying a mutant
allele (n > 5 or n < 5 repeats) showed increased AHR compared to AIA patients
with wild-type genotype (P=0.003). CONCLUSION: Although the alleles of the ALOX5
and ALOX5AP promoter cannot be considered as a prominent risk factor in the
development of AIA, the genetic variant of tandem repeat (GGGCGG; Sp1-binding
motif) in ALOX5 promoter is associated with the severity of airway
hyperresponsiveness in AIA patients.

PMID: 15876305 [PubMed - in process]


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2: Toxicol Sci. 2004 Dec;82(2):429-35. Epub 2004 Sep 1. 

EGR1 is a novel target for AhR agonists in human lung epithelial cells.

Martinez JM, Baek SJ, Mays DM, Tithof PK, Eling TE, Walker NJ.

Laboratory of Computational Biology and Risk Analysis, NIEHS, Research Triangle
Park, North Carolina 27709, USA. martine2@niehs.nih.gov

The transcription factor early growth response 1 (EGR1) was previously
identified as a potential novel target of 2,3,7,8-tetrachlorodibenzo-p-dioxin
(TCDD) in human lung epithelial cells by toxicogenomic analysis. EGR1 has been
implicated in the pathogenesis of vascular disease and is altered by a number of
factors that include stress, inflammation, and hypoxia. Depending on its
downstream targets or protein interactions, EGR1 regulates important biological
processes that include cell growth, apoptosis, and differentiation. The
following experiments were conducted to determine if EGR1 is indeed a target of
TCDD and polycyclic aromatic hydrocarbons (PAHs) that can act through a similar
mechanism. Pulmonary epithelial cells were exposed to TCDD for 24 h and an
increase in EGR1 mRNA was measured. In addition, EGR1 protein was increased by
TCDD and PAHs that have binding affinity to the aryl hydrocarbon receptor. The
transcriptional activity of the EGR1 promoter was measured with a luciferase
construct; however, no increases in luciferase activity were detected in TCDD or
PAH-treated cells. Using actinomycin to inhibit RNA synthesis, we found that
TCDD increased the half-life of EGR1 mRNA from 13 to 22 min. Thus, the increase
in EGR1 expression appears to be mediated through a post-transcriptional
mechanism that leads to the higher EGR1 protein levels in TCDD and PAH treated
cells, compared to vehicle treated cells. Increased expression of a
transcription factor EGR1 with tumorigenic and other biological activities could
contribute to the deleterious pulmonary effects of exposure to these
environmental agents.

PMID: 15342960 [PubMed - indexed for MEDLINE]


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