The tumor suppressor protein PTEN inhibits rat hepatic stellate cell activation.
BACKGROUND
Following a fibrogenic stimulus, the hepatic stellate cell (HSC) transforms from a quiescent to an activated cell type associated with increased proliferation, collagen and smooth muscle alpha-actin (alphaSMA) expression. Phosphatase and Tensin Homolog Deleted on Chromosome Ten (PTEN), a tumor suppressor phosphatase, has been shown to play a role in several nonmalignant diseases. Here, we investigated the role of PTEN during HSC activation.


METHODS
Rat HSCs 2 days after isolation were transduced with adenoviruses expressing either the wild-type (WT) or a dominant negative form of PTEN, and culture-associated activation of HSCs, including morphological changes, expression of alphaSMA and alpha1(I) collagen, and cell proliferation, were evaluated. Apoptosis of HSCs was detected by measuring activity of caspase 3/7. Phosphorylation status of Akt, p70(S6K), and Erk was detected by Western blotting.


RESULTS
Overexpression of WT-PTEN inhibited phenotypic changes were associated with HSC activation, including morphological changes, expression of alphaSMA and alpha1(I) collagen, and HSC proliferation, including cyclin D1 expression. WT-PTEN expression also induced apoptosis in HSCs with increased caspase 3/7 activity. Expression of WT-PTEN also caused decreased activation of Akt, p70(S6K), and Erk signaling pathways.


CONCLUSIONS
Taken together, these findings show that PTEN represents an important negative regulator for transactivation of HSCs. This may have important implications for the design of therapeutic strategies to prevent the progression of liver fibrosis.
Takashima
Motoki
M
Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina, CB #7032, Medical Biomolecular Research Building, Room 7340B, Chapel Hill, NC 27599-7032, USA.
Parsons
Christopher J
CJ
Ikejima
Kenichi
K
Watanabe
Sumio
S
White
Eric S
ES
Rippe
Richard A
RA
D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D049109:Cell Proliferation; D024042:Collagen Type I / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D009130:Muscle, Smooth / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
D000199:Actins; D024042:Collagen Type I; D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat