Isolation and characterization of a variant of B16‐mouse melanoma resistant to MSH growth inhibition

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Abstract
A variant of B‐16 F1 mouse melanoma was selected for its ability to survive and replicate in the presence of melanocyte‐stimulating hormone (MSH). Although the variant (MR‐4) was completely resistant to growth inhibition by MSH, cyclic AMP was still able to block cell replication. Tyrosinase activity in MR‐4 cells was considerably lower than in B‐16 F1 cells. MSH induced a twofold to three‐fold increase in tyrosinase activity in both cell types, but the absolute activity in MR‐4 remained significantly less than in the parental cells. MR‐4 cells were also found to have a markedly depressed cyclic AMP‐dependent protein kinase activity relative to B‐16 F1 cells. The protein kinase from both cell types was stimulated by cyclic AMP, but the level of MR‐4 kinase activity at maximal cyclic AMP concentrations remained considerably lower than B‐16 F1 kinase activity under the same conditions. In both cell types adenylate cyclase activity was markedly stimulated by MSH. When equal numbers of viable F1 and MR‐4 cells were injected subcutaneously into C57/B1 mice, the MR‐4 cells formed tumors earlier and killed the host sooner than the parental F1 cells. We conclude that the biochemical alteration which allows MR‐4 cells to replicate in the presence of MSH is a low level of tyrosinase activity, which in turn may be the result of low cyclic AMP‐dependent protein kinase activity.