Thioredoxin inhibits the tumor supressor, PTEN

DESCRIPTION (provided by applicant): Thioredoxin (Trx) is a small redox protein
overexpressed in many human cancers that stimulates cell growth and inhibits
programmed cell death (apoptosis). Trx expression is associated with aggressive
tumor growth and decreased patient survival. Trx interacts with a variety of
proteins, such as the apoptosis signaling kinase (ASK-1), NF-KB, the T7 DNA
polymerase and many transcription factors. Nevertheless, the mechanism(s) by
which Trx produces its effects are not known. I have identified a novel
potential mechanism for Trx?s effects, involving the redox inhibition of the
cell survival inhibitor PTEN. PTEN is a lipid phosphatase that antagonizes the
effects of phosphatidylinositol-3-kinase in activating Akt, a major pathway
inhibiting programmed cell death and promoting cancer cell survival. Reduced
but not oxidized Trx inhibits PTEN, indicating that redox activity is necessary
for the inhibition, and thioredoxin reductase reverses the inhibition. Docking
studies suggested that critical cysteine residues on Trx and on PTEN are
necessary for the inhibition of PTEN. Hence, Trx?s effects could be explained,
by the binding of Trx directly to PTEN and by its redox inhibition. The
objectives of my studies are to further investigate the mechanism of PTEN
inhibition by Trx in cancer cells and to examine the biological significance of
the interaction between PTEN and Trx in cancer cells.