Radiation-induced apoptosis and its role in tissue response

Abstract A question pertinent to carcinogenesis after low doses and tissue response after high doses is whether the apoptotically sensitive cells in cell lineages are a part of the stem cell population or a daughter population, and whether mutations that affect stem cell response also affect the cell population susceptible to apoptosis. This has now been addressed by using mice null for each of several genes important for radiation response and cell survival. In wild-type mice, an acute dose of ≥1 Gy induces apoptosis by 4 h in ≤6 cells situated in the stem-cell zone of each small-intestinal crypt in mice. In mice null for the damage-processing gene atm , the level of apoptoses induced by 1 Gy was lower than in wild-types. The distribution of apoptoses within the crypt was unaffected. In contrast, the clonogens killed by much higher doses were three-fold more sensitive than in +/+ mice (microcolony assay). In mice null for the apoptosis-promoting gene tp53 , the early wave of radiation-induced apoptosis was abolished. The crypts demonstrated a complex dose–survival curve, being more sensitive at lower doses and more resistant at higher doses, but not shifted totally in one direction or the other compared to +/+ animals. In mice null for the anti-apoptosis gene bcl-2 , the early wave of induced apoptosis was similar to in the +/+, but the clonogens were slightly more sensitive. This first report of apoptosis (and clonogen radiosensivity) in gut crypts of atm null mice indicates that radiation-induced apoptosis is both atm and p53 dependent. Also, the atm-null clonogens with markedly increased radiosensitivity either die via the second wave of (p53-independent) apoptosis and not the first wave, or by another mechanism such as premature differentiation or mitotic failure. The increased clonogen radiosensitivity in mice null for bcl-2 is compatible with its survival function, although bcl-2 has not been detected immunohistochemically in this site in +/+ mice. These data indicate the far greater importance of atm than two classical regulators of apoptosis, p53 and bcl-2, in the response of clonogens in the small intestine to high radiation doses. These studies show that the response of apoptotically susceptible cells at low dose, and clonogenic cells at high dose, can be differentially affected by particular mutations such as in atm. This suggests different modes of death of the two cell populations, and hence heterogeneity within precursor cell populations, which is a feature also of some other tissues.