Functional Association of Nm23-H1 Tumor Suppressor with Macrophage Migration Inhibitory Factor (MIF).

Here we report that Nm23-H1 tumor suppressor is an interacting partner of MIF in cells. The use of Nm23-H1 mutants (C4S, C109S, and C145S) and MIF mutants (C57S, C60S, and C81S) revealed that this interaction was significantly affected by C145S mutant of Nm23-H1 and C60S mutant of MIF, but not other Nm23-H1 and MIF mutants, suggesting that a disulfide linkage involving Cys145 of Nm23-H1 and Cys60 of MIF is responsible for Nm23-H1-MIF complex formation. In terms of biological significances, coexpression of MIF significantly inhibited Nm23-H1 biochemical activities such as autophosphorylation, phosphotransferase activity, and nucleoside-diphosphate kinase activity, whereas Nm23-H1-induced cell growth in HaCaT cells was enhanced by MIF. On the other hand, in addition to the inhibition of MIF-induced proliferation in NIH/3T3 cells, Nm23-H1 coexpression stimulated the D-dopachrome tautomerase activity of MIF. Moreover, Nm23-H1 rescued MIF-induced suppression of p53 activity and potentiated p53-mediated apoptosis though the enhancement of p53 stability and stimulation of p53 nuclear translocation. These results indicate that Nm23-H1 may be a potential negative modulator of MIF that is implicated in the regulation of inflammation and tumorigenesis. [ABSTRACT FROM AUTHOR]