in in vitro studies, such as those of Borek and others (1987) in which DNA isolated from radiation-transformed C3H10T1/2 cells was shown to transform recipient cells after transfection.

The molecular mechanisms of radiation-induced transformation are unknown. Several studies have used indirect methods to attempt to identify oncogenes in radiation-transformed cells (Guerrero and others 1984; Shuin and others 1986; Hall and Hei 1990). One approach has been to search DNA isolated from radiation-transformed cells for mutations in known oncogenes. In that way, K-ras and N-ras were shown to be activated in some of the mouse lymphomas induced by gamma radiation (Newcomb and others 1988); it is not known, however, whether these are the initial radiation-induced changes. Another approach has been to determine whether any known oncogenes are overexpressed in transformed cells. This requires measuring mRNA in known oncogenes. Two studies used the method to examine gamma-irradiated C3H10T1/2 cells (Schwab and others 1983; Krolewski and Little 1989). Each used several overexpressed, cloned oncogenes as probes, but they could not identify an oncogene; both speculated on the possibility that gamma radiation could activate an as-yet-unidentified oncogene. A more-recent direct approach to the question has been to isolate the oncogenes present in the transformed cells. Such an approach was used in an attempt to isolate an oncogene from gamma-irradiated C3H10T1/2 cells (Hall and Freyer 1991). Many cloned oncogenes have been tested by hybridization and were negative so the gene has not yet been identified. Later experiments by Hei and colleagues (1994b) showed that a single small dose of alpha particles (30 cGy of absorbed dose), corresponding to an average of a few particles per cell nucleus, can cause human bronchoepithelial cells to become tumorigenic. A dominant gene is involved, inasmuch as the phenotype can be transmitted by transfection. Again, no known oncogene has been identified. The data support the speculation that one or more as-yet-unknown oncogenes can be involved in radiation-induced transformation.


Suppressor genes act recessively: both copies must be lost or inactivated for the cell to express the malignant phenotype. Stanbridge (1976) showed that if a hybrid was made by fusing a normal human fibroblast to a malignant HeLa cell, the normal cell suppressed the expression of malignancy by the HeLa cell. It was shown further that if during the repeated subculture of the hybrid cells, chromosome 11 was lost, the malignant phenotype was restored. It was inferred that chromosome 11 in the normal human fibroblast contains a gene capable of suppressing the malignant phenotype. In later experiments, Saxon and colleagues (1986) injected microcells containing a single human chromosome 11 into HeLa cells and found that it suppressed their malignant phenotype; if chromosome 11 was lost from the cell, the malignant phenotype was restored.

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