Regulation of p53 tumor suppressor by Helicobacter pylori in gastric epithelial cells.
OBJECTIVE
Infection with the gastric mucosal pathogen Helicobacter pylori is the strongest identified risk factor for distal gastric cancer. These bacteria colonize a significant part of the world's population. We investigated the molecular mechanisms of p53 regulation in H pylori-infected cells.


METHODS
Mongolian gerbils were challenged with H pylori and their gastric tissues were analyzed by immunohistochemistry and immunoblotting with p53 antibodies. Gastric epithelial cells were co-cultured with H pylori and the regulation of p53 was assessed by real-time polymerase chain reaction, immunoblotting, immunofluorescence, and cell survival assays. Short hairpin RNA and dominant-negative mutants were used to inhibit activities of Human Double Minute 2 (HDM2) and AKT1 proteins.


RESULTS
We found that in addition to previously reported up-regulation of p53, H pylori can also negatively regulate p53 by increasing ubiquitination and proteasomal degradation via activation of the serine/threonine kinase AKT1, which phosphorylates and activates the ubiquitin ligase HDM2. These effects were mediated by the bacterial virulence factor CagA; ectopic expression of CagA in gastric epithelial cells increased phosphorylation of HDM2 along with the ubiquitination and proteasomal degradation of p53. The decrease in p53 levels increased survival of gastric epithelial cells that had sustained DNA damage.


CONCLUSIONS
H pylori is able to inhibit the tumor suppressor p53. H pylori activates AKT1, resulting in phosphorylation and activation of HDM2 and subsequent degradation of p53 in gastric epithelial cells. H pylori-induced dysregulation of p53 is a potential mechanism by which the microorganism increases the risk of gastric cancer in infected individuals.
Wei
Jinxiong
J
Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Nagy
Toni A
TA
Vilgelm
Anna
A
Zaika
Elena
E
Ogden
Seth R
SR
Romero-Gallo
Judith
J
Piazuelo
Maria B
MB
Correa
Pelayo
P
Washington
Mary K
MK
El-Rifai
Wael
W
Peek
Richard M
RM
Zaika
Alexander
A
D000818:Animals; D000942:Antigens, Bacterial / Q000502:physiology; D001426:Bacterial Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D005753:Gastric Mucosa / Q000382:microbiology*; D005849:Gerbillinae; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D013274:Stomach Neoplasms / Q000209:etiology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*; D014774:Virulence
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D016159:Tumor Suppressor Protein p53; C080866:cagA protein, Helicobacter pylori; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D051057:Proto-Oncogene Proteins c-akt