Inhibition of the Association with Nuclear Matrix of pRB, p70 and p40 Proteins Along with the Specific Suppression of c-MYC Expression by Geldanamycin, an Inhibitor of Src Tyrosine Kinase

Geldanamycin is an antibiotic that preferentially inhibits Gl/S transition and causes G2/M arrest in human leukemia HL-60 cells. With it, we selectively inhibited recombinant Src tyrosine kinase without significantly inhibiting protein kinase A. The perturbation of cell cycling by geldanamycin was accompanied by marked suppression of c-MYC expression. In contrast to this, pRB expression was remarkably enhanced by geldanamycin. In the untreated HL-60 cells, c-MYC was apparently enriched in nuclear matrix preparation, and significant amounts of hyperphosphorylated pRB, p70 and p40 proteins were observed to associate with the nuclear matrix. The amounts of these proteins associated with the nuclear matrix, however, were markedly decreased by treatment with geldanamycin. This finding suggests that the association of c-MYC, hyperphosphorylated pRB, p70 and p40 proteins with the nuclear matrix is essential in cell cycling, especially in Gl/S and G2/M progressions, and that this association is a part of signal transduction pathway in Src kinase activation.