Co-regulation of metastatic and transforming activity of normal and mutantras genes

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Abstract
We have analyzed the metastatic properties of NIH‐3T3 cells transformed by H‐ras activated through over‐expression and/or mutation. Our results reveal that elevated expression of H‐ras proto‐oncogene can induce the complete metastatic phenotype. Cells transformed by the proto‐oncogene have a lower metastatic potential than those transformed by a mutated ras gene. ras oncogenes activated through alterations in codon 12 which encode p21 molecules with impaired GTPase activity, or in codon 59 which produce p21 molecules that release bound guanine nucleotides faster, or in codon 61 which produce p21 having impaired GTPase activity and altered nucleotide release properties, are all able to induce the metastatic phenotype. Leucine‐61‐activated oncogenes with an additional mutation in codons 116, 117 or 119, resulting in a reduced affinity for guanine nucleotides, are also capable of inducing metastatic behavior. These data indicate that ras genes which are capable of transforming are also capable of inducing the full metastatic phenotype in NIH‐3T3 cells. This suggests that both phenotypes are induced through an increase in p21‐GTP concentration in ras‐transformed cells. This established model for ras‐mediated transformation can also explain the qualitative and quantitative regulation of metastatic behavior by ras.