Abnormal PTEN expression in portal hypertensive gastric mucosa: A key to impaired PI 3‐kinase/Akt activation and delayed injury healing?
Abnormal PTEN expression in portal hypertensive gastric mucosa: A key to impaired PI 3‐kinase/Akt activation and delayed injury healing?
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DOI：
10.1096/fj.02-1107fje
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发表时间：
2003-12
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通讯作者：
K. Tsugawa;Michael K. Jones;T. Akahoshi;W. Moon;Yoshihiko Maewhara;M. Hashizume;I. Sarfeh;A. Tarnawski
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作者：
K. Tsugawa;Michael K. Jones;T. Akahoshi;W. Moon;Yoshihiko Maewhara;M. Hashizume;I. Sarfeh;A. Tarnawski
第十号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）是一种对磷酸化肽和磷脂都具有活性的双特异性磷酸酶。PTEN抑制Akt的活化，Akt是PI 3-激酶的下游效应物，其是细胞增殖、迁移、存活和组织损伤愈合所必需的血管生成的组成部分。损伤愈合过程中的PTEN表达和激活仍未探索。门静脉高压症（PHT）胃粘膜损伤后愈合不良，但其机制尚不清楚。我们研究了受损的PHT胃粘膜的愈合受损是否是由于异常的PTEN表达/活化导致Akt活化降低。我们还研究了Egr-1的可能参与，Egr-1在一些细胞中调节PTEN（例如，胎肾上皮细胞）和TNF-α，其可诱导Egr-1表达。在PHT胃粘膜损伤后6 h，与正常胃粘膜相比，PTEN蛋白水平增加2.7倍;未磷酸化的PTEN（反映活化的PTEN）增加2.4倍; Akt磷酸化（反映Akt活化）减少2倍; Egr-1表达增加3.3倍。TNF-α中和作用逆转了PHT胃粘膜中的所有上述异常，减少了粘膜损伤，并促进了愈合。我们的结论是，在损伤的PHT胃粘膜中，过表达/活化的PTEN导致PI 3-激酶/Akt通路的活化减少，从而导致损伤愈合受损。
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‐α, 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‐α 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.