Spontaneous activation of a human proto-oncogene.

Abstract

Malignant activation of the c-has/bas proto-oncogene in T24 human bladder carcinoma cells was mediated by a single point mutation. A deoxyguanosine located at position 35 of the 1st exon of this proto-oncogene was substituted by thymidine. These findings predicted that the resulting oncogene would code for a structurally altered p21 protein containing valine instead of glycine as its 12th amino acid residue. The spontaneous activation of the human c-has/bas proto-oncogene during transfection of NIH/3T3 cells is reported. As in T24 cells, this in vitro activated oncogene also acquired malignant properties by a single point mutation. A G .fwdarw. A transition was detected, which occurred at the same position as the mutation responsible for the activation of the T24 oncogene. The p21 protein coded for by the spontaneously activated c-has/bas gene will probably incorporate aspartic acid as its 12th amino acid residue. Computer analysis of the secondary structure of c-has/bas-encoded p21 proteins indicates that by substitution of the glycine residue located at position 12, by aspartic acid or valine and also by any other amino acid, would result in the same structural alteration. A specific conformational change is apparently sufficient to confer transforming properties to this p21 protein. They predict that any mutation affecting the coding properties of the 12th codon of the c-has/bas proto-oncogene will lead to its malignant activation.