We have previously reported that upregulated expression of several RNases in DON-treated RAW 264.7 cells occurs prior to or simultaneously with rRNA degradation (Li and Pestka, 2008) . Particularly notable was RNase L, an enzyme that can mediate inhibition of protein synthesis, apoptosis induction, and antiviral activity (Stark et al., 1998) . Although RNase L is activated by a number of stressors, its only known endogenous direct activator is 2-5A, a product of oligoadenylate synthetase (Pandey et al., 2004; Liang et al., 2006) . Upon binding to 2-5A, RNase L is activated by dimerization and possibly inhibits protein synthesis via the degradation of both messenger RNA and 28S rRNA (Clemens and Vaquero, 1978; Wreschner et al., 1981) . We found that under cell-free conditions in the presence of 2-5A, RNase L readily cleaved both FRET probe and purified rRNA; however, it did not degrade rRNA in The observation that p38 but not JNK mediated DONinduced rRNA cleavage is consistent with previous observations that p38 is a central regulator of cell fate in DON-exposed macrophages (Zhou et al., 2005a) . Our findings further demonstrate that PKR and Hck also mediate DON-induced rRNA cleavage. Although crosstalk between PKR and Hck is still not completely understood, these kinases are wellestablished upstream mediators of DON-induced p38 activation (Zhou et al., 2003b (Zhou et al., , 2005b . These data are consistent with our previous observations that 40S ribosome subunit-associated PKR, Hck, and p38 are activated upon DON exposure (Bae et al., 2010) .