INHIBITION OF THE ASSOCIATION WITH NUCLEAR MATRIX OF PRB, P70 AND P40PROTEINS ALONG WITH THE SPECIFIC SUPPRESSION OF C-MYC EXPRESSION BY GELDANAMYCIN, AN INHIBITOR OF SRC TYROSINE KINASE

Geldanamycin is an antibiotic that preferentially inhibits G1/S transi tion and causes G2/M arrest in human leukemia HL-60 cells. With it, we selectively inhibited recombinant Src tyrosine kinase without signifi cantly inhibiting protein kinase A. The perturbation of cell cycling b y geldanamycin was accompanied by marked suppression of c-MYC expressi on. In contrast to this, pRB expression was remarkably enhanced by gel danamycin. In the untreated HL-60 cells, c-MYC was apparently enriched in nuclear matrix preparation, and significant amounts of hyperphosph orylated pRB, p70 and p40 proteins were observed to associate with the nuclear matrix. The amounts of these proteins associated with the nuc lear matrix, however, were markedly decreased by treatment with geldan amycin. This finding suggests that the association of c-MYC, hyperphos phorylated pRB, p70 and p40 proteins with the nuclear matrix is essent ial in cell cycling, especially in G1/S and G2/M progressions, and tha t this association is a part of signal transduction pathway in Src kin ase activation.