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

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, Co[Cl.sub.2]-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. APE1; HIF1[alpha]; Mcl1; H. pylori; gastric cancer doi: 10.1152/ajpgi.00372.2010.