Regulation of complement C3 gene in the human hepatoma cells HepG2 under oxidative stress

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Аннотация

Accumulation of reactive oxygen and nitrogen species in cells during oxidative stress leads to oxidative damage to various cellular components, including DNA, proteins, and lipids, and, as a consequence, to the development of a number of severe diseases, such as atherosclerosis. Protein C3 is a central component of the complement cascade and a key player in the immune system. Proinflammatory activity of C3 can also contribute to the development of metabolic syndrome. Although hepatocytes are the main source of C3 in blood, regulation of C3 gene expression in hepatocytes under oxidative stress remains unexplored. Here we observe the suppression of C3 transcription and secretion during hydrogen peroxide-induced oxidative stress in human hepatoma cells HepG2. Transcription factor FOXO1 promoted C3 expression, and C3 repression by oxidative stress was mediated through regulation of FOXO1/HNF4α complex binding to the C3 promoter. We identified a novel cluster of FOXO1 binding sites in the distal region of the C3 promoter that was essential for regulation of C3 expression by FOXO1/HNF4α complex. Further, activation of the main MAP kinase cascades (ERK1/2, p38, and JNK), AMP kinase and the transcription factor NF-κB were necessary for suppression of C3 during oxidative stress. Together, we identified molecular mechanisms and transcription factors that mediate suppression of C3 production in HepG2 cells during oxidative stress.

Авторлар туралы

A. Babina

Institute of Experimental Medicine

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia

V. Shavva

Institute of Experimental Medicine

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia

A. Lisunov

Institute of Experimental Medicine; St. Petersburg State University

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia; St. Petersburg, 199034 Russia

G. Oleinikova

Institute of Experimental Medicine

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia

E. Larionova

Institute of Experimental Medicine

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia

A. Dmitrieva

Institute of Experimental Medicine

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia

E. Nekrasova

Institute of Experimental Medicine

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia

S. Orlov

Institute of Experimental Medicine; St. Petersburg State University

Email: serge@iem.spb.ru
St. Petersburg, 197376 Russia; St. Petersburg, 199034 Russia

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