Regulation of the activity of the tumor suppressor PTEN by thioredoxin in Drosophila melanogaster.
Human Thioredoxin-1 (hTrx-1) is a small redox protein with a molecular weight of 12 kDa that contains two cysteine residues found in its catalytic site. HTrx-1 plays an important role in cell growth, apoptosis, and cancer patient prognosis. Recently, we have demonstrated that hTrx-1 binds to the C2 domain of the human tumor suppressor, PTEN, in a redox dependent manner. This binding leads to the inhibition of PTEN lipid phosphatase activity in mammalian tissue culture systems. In this study, we show that over-expression of hTrx-1 in Drosophila melanogaster promotes cell growth and proliferation during eye development as measured by eye size and ommatidia size. Furthermore, hTrx-1 rescues the small eye phenotype induced by the over-expression of PTEN. We demonstrate that this rescue of the PTEN-induced eye size phenotype requires cysteine-218 in the C2 domain of PTEN. We also show that hTrx-1 over-expression results in increased Akt phosphorylation in fly head extracts supporting our observations that the hTrx-1-induced eye size increase results from the inhibition of PTEN activity. Our study confirms the redox regulation of PTEN through disulfide bond formation with the hTrx-1 in Drosophila and suggests conserved mechanisms for thioredoxins and their interactions with the phosphatidylinositol-3-kinase signaling pathway in humans and fruit flies.
Song
Zuohe
Z
Arizona Cancer Center, University of Arizona, 1515 N. Campbell Blvd., Tucson, AZ 85724, USA.
Saghafi
Negin
N
Gokhale
Vijay
V
Brabant
Marc
M
Meuillet
Emmanuelle J
EJ
D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation; D003545:Cysteine / Q000737:chemistry; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000201:enzymology*; D005123:Eye / Q000166:cytology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D008969:Molecular Sequence Data; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D029721:Drosophila Proteins; C491203:TXN protein, human; D025521:Tumor Suppressor Proteins; D013879:Thioredoxins; D051059:PTEN Phosphohydrolase; C487101:PTEN protein, Drosophila; D003545:Cysteine