Cyclin-dependent kinase 2 and cyclin A interaction with E2F are targets for tyrosine induction of B16 melanoma terminal differentiation.

L-Tyrosine promotes a dramatic increase in melanogenesis and an apparent replicative senescence in B16 melanoma (M. Strasberg-Rieber and M. Rieber, Cancer Res., 53:2469-2471, 1993). Since cyclins are implicated in controlling cell proliferation and differentiation, we have now investigated their relationship to melanocytic growth arrest and pigmentation. In B16 melanoma cells enriched in G1 by serum starvation or synchronized in late G1/early S phase by exposure to hydroxyurea, L-tyrosine overrides mitogenic signals and induces terminal differentiation without cytotoxicity. This correlates with a decrease in cyclin A and cyclin E-dependent kinase 2 activity and with an altered interaction of cyclin A with the transcription factor E2F. This activity involves a lower level of the catalytic cdK2 kinase protein without a concomitant decrease in cyclin A or cyclin E. Upon addition of serum or removal of hydroxyurea, cells resume cell cycle progression and the ability to form tumors in vivo, but these properties are irreversibly inhibited in tyrosine-treated cells. Our data suggest that targeted inactivation of cdK2 with specific inducers of differentiation favors reacquisition of tumor growth control.