Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis
Cytokine suppression of protease activation in wild-type p53-dependent and p53-independent apoptosis
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DOI：
10.1073/pnas.94.17.9349
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发表时间：
1997-08-19
影响因子：
11.1
通讯作者：
Sachs, L
中科院分区：
文献类型：
--
作者：
Lotem, J;Sachs, L
过表达野生型p53的M1髓性白血病细胞发生凋亡，这种凋亡可被某些细胞因子、蛋白酶抑制剂和抗氧化剂抑制。我们现在发现，过表达野生型p53诱导细胞凋亡与白细胞介素-1 β转化酶（ICE）样蛋白酶的激活有关，导致多聚腺苷酸的裂解。（ADP-核糖）聚合酶和ICE样蛋白酶Nedd-2的酶原，这些蛋白酶的激活和细胞凋亡被细胞因子白细胞介素6或细胞因子干扰素γ和抗氧化剂丁基化的组合抑制。羟基苯甲醚和聚的活化在不表达p53的M1细胞克隆中，长春新碱或多柔比星诱导的蛋白酶激活和凋亡不被蛋白酶抑制剂抑制，但被白细胞介素6抑制，在另一种髓性白血病（7-M12）中，多柔比星也诱导蛋白酶激活和细胞凋亡，这些蛋白酶激活和细胞凋亡不受蛋白酶抑制剂的抑制，但受粒细胞-巨噬细胞集落刺激因子的抑制。结果表明：（i）野生型p53本身的过表达或用细胞毒性化合物处理野生型p53表达或p53不表达的髓性白血病细胞与ICE样蛋白酶的活化有关;（ii）细胞因子在蛋白酶活化的上游发挥细胞凋亡抑制功能;（iii）细胞毒性化合物诱导细胞凋亡的额外途径;和（iv）细胞因子也可以抑制凋亡机制的这些其它组分。
M1 myeloid leukemic cells overexpressing wild-type p53 undergo apoptosis, This apoptosis can be sup pressed by some cytokines, protease inhibitors, and antioxidants. We now show that induction of apoptosis by overexpressing wild-type p53 is associated with activation of interleukin-1 beta-converting enzyme (ICE)-like proteases, resulting in cleavage of poly(ADP-ribose) polymerase and the proenzyme of the ICE-like protease Nedd-2, Activation of these proteases and apoptosis were suppressed by the cytokine interleukin 6 or by a combination of the cytokine interferon gamma and the antioxidant butylated hydroxyanisole, and activation of poly(ADP-ribose) polymerase and apoptosis were suppressed by some protease inhibitors, In a clone of M1 cells that did not express p53, vincristine or doxorubicin induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by interleukin 6, In another myeloid leukemia (7-M12) doxorubicin also induced protease activation and apoptosis that were not suppressed by protease inhibitors, but were suppressed by granulocyte-macrophage colony-stimulating factor. The results indicate that (i) overexpression of wild-type p53 by itself or treatment with cytotoxic compounds in wild-type p53-expressing or p53-nonexpressing myeloid leukemic cells is associated with activation of ICE-like proteases; (ii) cytokines exert apoptosis-suppressing functions upstream of protease activation; (iii) the cytotoxic compounds induce additional pathways in apoptosis; and (iv) cytokines can also suppress these other components of the apoptotic machinery.