Mechanism of hypoxia-inducible factor 1 alpha-mediated Mcl1 regulation in Helicobacter pylori-infected human gastric epithelium.
Am J Physiol Gastrointest Liver Physiol
; 299(5): G1177-86, 2010 Nov.
Article
en En
| MEDLINE
| ID: mdl-20829524
ABSTRACT
Hypoxia-inducible factor 1 (HIF1) consists of a hypoxia-inducible α subunit and a constitutively expressed ß subunit. Reactive oxygen species (ROS) induced by Helicobacter pylori stabilize HIF1α in the human gastric epithelium in normoxia. HIF1α 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 HIF1α 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 HIF1α 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 HIF1α, further transcriptional activation of mcl1 was not observed. We identified a HIF-binding site (HBS) in the hif1α promoter and showed that increased HIF1α expression, whether H. pylori-induced or hypoxia-mimetic agent, CoCl(2)-induced, resulted in enhanced HIF1α binding to its own promoter. This resulted in a transcriptionally inactive hif1α promoter since hif1α HBS lacks HIF ancillary sequence (HAS) required for HIF1 transcriptional activity. We conclude that enhanced binding of "nonfunctional" HIF1α to hif1α promoter and limiting availability of p300 in the cell serves as checkpoints for uncontrolled HIF1α activity.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Helicobacter pylori
/
Infecciones por Helicobacter
/
Proteínas Proto-Oncogénicas c-bcl-2
/
Células Epiteliales
/
Subunidad alfa del Factor 1 Inducible por Hipoxia
/
Mucosa Gástrica
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Am J Physiol Gastrointest Liver Physiol
Asunto de la revista:
FISIOLOGIA
/
GASTROENTEROLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos