Abnormal PTEN expression in portal hypertensive gastric mucosa: a key to impaired PI 3-kinase/Akt activation and delayed injury healing?
Phosphatase and tensin homologue deleted on chromosome ten (PTEN) is a dual-specificity phosphatase that has activity toward both phosphorylated peptides and phospholipids. PTEN inhibits activation of Akt, the downstream effector of PI 3-kinase, which is integral to cell proliferation, migration, survival, and angiogenesis essential for tissue injury healing. PTEN expression and activation during injury healing remain unexplored. Portal hypertensive (PHT) gastric mucosa has impaired injury healing, but the underlying mechanisms remain unknown. We investigated whether impaired healing of injured PHT gastric mucosa is due to abnormal PTEN expression/activation that leads to decreased Akt activation. We also investigated the possible involvement of Egr-1, which regulates PTEN in some cells (e.g., fetal kidney epithelial cells), and TNF-alpha, which can induce Egr-1 expression. In PHT gastric mucosa 6 h after injury, PTEN protein levels were increased by 2.7-fold; unphosphorylated PTEN (reflecting activated PTEN) was increased by 2.4-fold; Akt phosphorylation (reflecting Akt activation) was reduced by 2-fold; and Egr-1 expression was increased by 3.3-fold vs. normal gastric mucosa. TNF-alpha neutralization reversed all of the above abnormalities in PHT gastric mucosa, reduced mucosal injury, and enhanced healing. We conclude that, in injured PHT gastric mucosa, overexpressed/activated PTEN leads to the reduced activation of the PI 3-kinase/Akt pathway that results in impaired injury healing.
Tsugawa
Kouji
K
Department of Medicine, Department of Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
Jones
Michael K
MK
Akahoshi
Tomohiko
T
Moon
Woo Sung
WS
Maehara
Yoshihiko
Y
Hashizume
Makoto
M
Sarfeh
I James
IJ
Tarnawski
Andrzej S
AS
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D004789:Enzyme Activation; D000431:Ethanol; D005753:Gastric Mucosa / Q000201:enzymology* / Q000502:physiology; D006975:Hypertension, Portal / Q000139:chemically induced / Q000201:enzymology*; D017874:Immediate-Early Proteins; D007700:Kinetics; D008954:Models, Biological; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014945:Wound Healing
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; D000431:Ethanol; D017874:Immediate-Early Proteins; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D010744:Phosphoric Monoester Hydrolases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C486110:Egr1 protein, rat; C494920:Akt1 protein, rat