Mechanism of hypoxia-inducible factor 1α-mediated Mcl1 regulation in Helicobacter pylori-infected human gastric epithelium

Bhattacharyya A, Chattopadhyay R, Hall EH, Mebrahtu ST, Ernst PB, Crowe SE. Mechanism of hypoxia-inducible factor 1 alpha-mediated Mcl1 regulation in Helicobacter pylori-infected human gastric epithelium. Am J Physiol Gastrointest Liver Physiol 299: G1177-G1186, 2010. First published September 9, 2010; doi: 10.1152/ajpgi.00372.2010.-Hypoxia-inducible factor 1 (HIF1) consists of a hypoxia-inducible alpha subunit and a constitutively expressed beta subunit. Reactive oxygen species (ROS) induced by Helicobacter pylori stabilize HIF1 alpha in the human gastric epithelium in normoxia. HIF1 alpha plays crucial role in carcinogenesis and has been associated with malignant progression of gastric cancer. Several genes contain functional hypoxia-response elements (HREs) in their promoters including Bcl2 family member, Mcl1. Cellular ratios of antiapoptotic oncogenic protein, Mcl1, and tumor suppressor proapoptotic protein, Noxa, determine cell fate by regulating normal cellular growth, cell death and oncogenic processes. The aim of the present study was to examine the mechanism of HIF1 alpha induction in the H. pylori-infected gastric epithelium to better understand disease pathogenesis by H. pylori relevant to gastric carcinogenesis. Our data showed that the dose-dependent increase in HIF1 alpha in H. pylori-infected gastric epithelia is mediated by induction of a ROS-inducible protein, apurinic/apyrimidinic endonuclease 1 (APE1), and an enhanced interaction of APE1 with the transcriptional coactivator p300. Surprisingly, with accumulation of HIF1 alpha, further transcriptional activation of mcl1 was not observed. We identified a HIF-binding site (HBS) in the hif1 alpha promoter and showed that increased HIF1 alpha expression, whether H. pylori-induced or hypoxia-mimetic agent, CoCl2-induced, resulted in enhanced HIF1 alpha binding to its own promoter. This resulted in a transcriptionally inactive hif1 alpha promoter since hif1 alpha HBS lacks HIF ancillary sequence (HAS) required for HIF1 transcriptional activity. We conclude that enhanced binding of nonfunctional HIF1 alpha to hif1 alpha promoter and limiting availability of p300 in the cell serves as checkpoints for uncontrolled HIF1 alpha activity.