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A Latent M_r 94,000 Gelatin-degrading Metalloprotease Induced during Differentiation of HL-60 Promyelocytic Leukemia Cells: A Member of the Collagenase Family of Enzymes

Laboratory of Pathology, National Cancer Institute [G. E. D.], and Clinical Neuroscience Branch, National Institute of Mental Health [B. M. M.], NIH, Bethesda, Maryland 20892

The treatment of HL-60 promyelocytic leukemia cells with phorbol esters (12-O-tetradecanoylphorbol-13-acetate) results in the appearance of cell substrate adhesion and the release of a M_r 94,000 gelatin-degrading metalloprotease. The appearance of the metalloprotease in the culture medium directly correlates with the timing and extent of cell substrate adhesion over a 24-h period. Anti-M_r 94,000 metalloprotease blocking antibodies were unable to interfere with the HL-60 cell substrate adhesion induced by 12-O-tetradecanoylphorbol-13-acetate, although they were able to specifically remove the M_r 94,000 gelatin-degrading activity from either HL-60 or U-937 cell-conditioned medium. A purified metalloprotease preparation was found to be predominantly latent and activated by organomercurials, acid treatment (pH 2 to 3.6), or 8 M urea. The activating effect of the latter two denaturing treatments suggests that conformational changes may be the common activating mechanism. The different treatments also caused the appearance of lower molecular weight gelatin-degrading bands (in gelatin zymogram gels) in a manner consistent with the autocatalytic cleavage that occurs with other collagenase proenzymes during activation. Edman degradation of a cyanogen bromide fragment from the M_r 94,000 metalloprotease provided the amino acid sequence [PR(C)GVPD] which is present in type I collagenase, stromelysin, and transin proenzyme sequences and partially conserved (V N substitution) in the type IV collagenase proenzyme. This sequence has been reported to be important in the maintenance of the latent state of the transin proenzyme (R. Sanchez-Lopez et al., J. Biol. Chem., 263: 11892–11899, 1988) and is a sequence unique to collagenase proenzymes. The N-terminal sequence of the M_r 94,000 metalloprotease (APQDQST) is unique and distinct from other collagenases. Thus, the M_r 94,000 metalloprotease from HL-60 cells appears to be a distinct and new member of the collagenase family of proteases.

¹ To whom requests for reprints should be addressed, at Cancer Research Center, La Jolla Cancer Research Foundation, 10901 N. Torrey Pines Rd., La Jolla, CA 92037.

Received 6/22/89. Revised 10/23/89. Accepted 11/13/89.

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