PMID: 9434101Jan 20, 1998Paper

Mutation in an alpha1-antitrypsin enhancer results in an interleukin-6 deficient acute-phase response due to loss of cooperativity between transcription factors

Biochimica Et Biophysica Acta
K MorganN A Kalsheker

Abstract

We previously reported that a mutation in a 3' enhancer region of the alpha1-antitrypsin (AAT) gene is associated with chronic obstructive airways disease (COAD). During the acute-phase response the plasma concentration of AAT increases approximately 3-fold and this effect is mediated primarily by interleukin-6 (IL-6). We demonstrate, by transfection of Hep G2 cells, that the AAT gene contains at least two enhancers, one at the 5' end of the gene which is dominant under basal conditions, and another at the 3' end of the gene which exhibits weak basal activity. However, both enhancers must be present to modulate the IL-6-induced response which is diminished as a consequence of the 3' enhancer mutation. These results suggest that the 3' enhancer modulates the IL-6 response through an interaction with the 5' enhancer. The mutation occurs at a DNA binding site for the ubiquitous transcription factor octamer-1 (Oct-1) and results in a loss of cooperativity between Oct-1 and the tissue-specific transcription factor, NF-IL6 (C/EBPbeta), a member of the C/EBP family of transcription factors. NF-IL6 is a key transcription factor for a major pathway through which IL-6 mediates its effects. These observations provide a novel mechanism for...Continue Reading

References

Jun 13, 1987·British Medical Journal·N A KalshekerR A Stockley

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Citations

May 7, 1998·The International Journal of Biochemistry & Cell Biology·K Morgan, N A Kalsheker
May 6, 1999·American Journal of Respiratory and Critical Care Medicine·A J SandfordP D Paré
Apr 12, 2003·American Journal of Respiratory Cell and Molecular Biology·Despina D FrangoliasAndrew J Sandford
Mar 12, 2013·Cell Communication & Adhesion·Gaetano CaramoriIan Adcock
Feb 24, 2001·Clinics in Chest Medicine·A J Sandford, P D Paré
Feb 27, 2014·The International Journal of Biochemistry & Cell Biology·Loic GuillotHarriet Corvol
Apr 15, 2003·Arteriosclerosis, Thrombosis, and Vascular Biology·Philippa J TalmudUNKNOWN Diabetes Atherosclerosis Intervention Study Investigators
Apr 15, 2011·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Andrea VecchiolaGisella Borzone
Feb 15, 2002·Current Opinion in Pulmonary Medicine·Andrew J SandfordPeter D Paré
Jun 10, 2016·International Journal of Endocrinology and Metabolism·Abdul Rehman Khan, Fazli Rabbi Awan

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