Shetty S, Velusamy T, Shetty RS, Marudamuthu AS, Shetty SK, Florova G, Tucker T, Koenig K, Shetty P, Bhandary YP, Idell S
Posttranscriptional Regulation of Plasminogen Activator Inhibitor-1 Expression in Human Pleural Mesothelial Cells. [JOURNAL ARTICLE]
Am J Respir Cell Mol Biol 2009 Oct 23.
The plasminogen activator inhibitor (PAI-1) effectively blocks the activities of both free and receptor bound urokinase-type plasminogen activator (uPA). Incubation of cultured human pleural mesothelial (Met5A) cells with TGF-beta increased PAI-1 protein. TGF-betabeta-globin mRNA, indicating that the binding sequence accelerates decay of endogenous PAI-1 mRNA. Competitive inhibition by overexpression of the 33 nt binding sequence in MeT5A cells reduced PAI-1 mRNA decay and increased PAI-1 protein and mRNA expression, indicating that the PAI-1 mRNABp destabilizes PAI-1 mRNA by its interaction with the endogenous 33 nt binding sequence. Incubation of Met5A cells with TGF-beta attenuated the interaction of the PAI-1 mRNABp with the 33 nt sequence. By conventional and affinity purification, we isolated the PAI-1 mRNABp and confirmed its identity as 6-Phospho-D-Gluconate-NADP oxidoreductase (6-PGD). 6-PGD specifically interacts with the full length as well as the 33 nt sequence of the PAI-1 mRNA 3'UTR. This newly recognized pathway could influence expression of PAI-1 by mesothelial or mesothelioma cells at the level of mRNA stability in the context of pleural inflammation or malignancy.
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