THE APOPTOSIS-ASSOCIATED GAMMA-RAY RESPONSE OF BCL-X(L) DEPENDS ON NORMAL P53 FUNCTION

We have investigated the effect of DNA damage on the expression of BCL -X, a member of the BCL-2 family. BCL-X mRNA levels were found to incr ease upon exposure human cells to ionizing radiation (IR). The Bcl-X(L ) protein, but not Bcl-X(S), was identified to be induced by IR. Like BAX, another member of the BCL-2 family and a p53-regulated gene, the induction of BCL-X(L) was dependent on normal p53 function and require d that cells have an apoptosis-susceptible phenotype. The induction of BCL-X(L) was rapid, transient and dose-dependent. The mRNA level peak ed at 4 h and returned to baseline by 24 h post-irradiation. In agreem ent with the increased transcript level, Bcl-X(L) protein level was al so observed to increase in cells with wild-type p53 where IR triggered apoptosis. In addition, a survey of the BCL-X(L) mRNA basal levels in human cells with known apoptotic responses showed that low basal leve ls of BCL-X(L) mRNA in cells were highly correlated with a strong abil ity of cells to undergo IR-induced apoptosis. On the other hand, high levels of basal BCL-X(L) were correlated,vith the resistance of cells to IR-induced apoptosis regardless of p53 status. These results indica te that BCL-2 and BCL-X(L) behave differently in response to DNA damag e treatment even though they both are able to protect cells from p53-m ediated apoptosis; along with down-regulation of BCL-2, BCL-X(L) was u p-regulated by IR in human cells with wild-type p53 and susceptibility to IR-induced apoptosis. We speculate that the physiological function of increased BCL-X(L) protein would be expected to probably limit the severity and length of BAX effect in order to maintain a proper thres hold for apoptosis and to complete cell cycle arrest activated by p53.