Beta-2-adrenergic receptor polymorphisms in cystic fibrosis.

OBJECTIVES: Cystic fibrosis (CF), an autosomal recessive disease affecting the lung, pancreas, gut, liver, and reproductive tract, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cyclic adenosine 3', 5' monophosphate-regulated chloride channel. The variability of disease progression among patients with CF suggests effects of genetic modifiers of disease. Beta-2 adrenergic receptors (beta2AR), which are abundant in airway epithelial cells, accelerate the formation of cyclic adenosine 3', 5' monophosphate, which can modulate CFTR activity and affect smooth muscle contractility. We tested the hypothesis that genetic variants of the beta2AR gene, which have been shown to influence receptor desensitization, are more frequent in patients than in controls. METHODS: We genotyped 130 adult CF patients and 1 : 1 age-matched, sex-matched, and ethnicity-matched normal volunteers for GlyArg and GlnGlu beta2AR. RESULTS: We found that CF patients were more likely than controls to be Gly homozygotes (48 and 32%, respectively) (P<0.01) and Glu homozygotes (29 and 10%, respectively) (P<0.01). CONCLUSIONS: Our results, showing a higher frequency of Gly and Glu beta2AR alleles in adult CF patients than in the control population, contrast with data from children with CF, who are reported to have lower frequency of Gly and similar frequency of G1u, and with data from young adults with CF, who showed no differences in frequencies of beta2AR variants. The GlyGlu variant of beta2AR may have properties that lead to enhanced beta2AR function, resulting in the upregulation of CFTR activity and the improvement of CF disease.

Elucidation of the c-Jun N-terminal kinase pathway mediated by Estein-Barr virus-encoded latent membrane protein 1.

Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis and nasopharyngeal carcinoma. EBV-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for cellular transformation caused by EBV. Expression of LMP1 in host cells constitutively activates both the c-Jun N-terminal kinase (JNK) and NF-kappaB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on overexpression studies with various dominant-negative constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knockout mice and the small interfering RNA technique, we find that the LMP1-mediated JNK pathway is distinct from those mediated by either TNF-alpha or interleukin-1. Moreover, we have further elucidated the LMP1-mediated JNK pathway by demonstrating that LMP1 selectively utilizes TNF receptor-associated factor 6, TAK1/TAB1, and c-Jun N-terminal kinase kinases 1 and 2 to activate JNK.