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2.4 Discovery of the H-ras gene

Consider the H-ras gene The oncogene that had been cloned from human bladder carcinoma cells caused transformation of NIH 3T3 cells, while its normal proto-oncogene counterpart (i.e., the normal Hras gene) lacked this ability. A 350-bp segments from the proto-oncogene and oncogene were subjected to DNA sequence analysis. The critical difference was extraordinarily subtle - a single base substitution in which a G (guanosine) residue in the proto-oncogene was replaced by a T (thymidine) in the oncogene. This single base-pair replacement - a point mutation - appeared to be all that was required to convert the normal gene into a potent oncogene Point mutation of the H-ras gene This was the first time that a mutation was discovered in a gene that contributed causally to the neoplastic growth of a human cancer. Equally important, it seemed that this genetic change arose as a somatic mutation. The ras point mutation established a mechanism for oncogene activation Within a decade, a large number of human tumors were found that carried point mutations in one of the three ras genes present in the mammalian genome: H-ras, K-ras, and N-ras. Significantly, in each of these tumors, the point mutation that was uncovered was present in one of three specific codons Consequently, all Ras oncoproteins were found to carry amino acid substitutions in residues 12, 61, or (less frequently) 13, Taken together, more than 20% of human tumors arising in a variety of tissues carry such point-mutated ras genes