Han Z, Chatterjee D, He D M, Early J, Pantazis P, Wyche J H, Hendrickson E A
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA.
Mol Cell Biol. 1995 Nov;15(11):5849-57. doi: 10.1128/MCB.15.11.5849.
The p53 tumor suppressor gene is thought to be required for the induction of programmed cell death (apoptosis) initiated by DNA damage. We show here, however, that the human promyelocytic leukemia cell line HL-60, which is known to be deficient in p53 because of large deletions in the p53 gene, can be induced to undergo apoptosis following X-irradiation. We demonstrate that the decision to undergo apoptosis in this cell line appears to be made at a G2 checkpoint. In addition, we characterize an HL-60 variant, HCW-2, which is radioresistant. HCW-2 cells display DNA damage induction and repair capabilities identical to those of the parental HL-60 cell line. Thus, the difference between the two cell lines appears to be that X-irradiation induces apoptosis in HL-60, but not in HCW-2, cells. Paradoxically, HCW-2 cells display high levels of expression of bax, which enhances apoptosis, and no longer express bcl-2, which blocks apoptosis. HCW-2 cells' resistance to apoptosis may be due to the acquisition of expression of bcl-XL, a bcl-2-related inhibitor of apoptosis. In summary, apoptosis can be induced in X-irradiated HL-60 cells by a p53-independent mechanism at a G2 checkpoint, despite the presence of endogenous bcl-2. The resistance shown by HCW-2 cells suggests that bcl-XL can block this process.
p53肿瘤抑制基因被认为是DNA损伤引发的程序性细胞死亡（凋亡）诱导过程所必需的。然而，我们在此表明，人早幼粒细胞白血病细胞系HL-60，因其p53基因存在大片段缺失而已知缺乏p53，在X射线照射后可被诱导发生凋亡。我们证明，该细胞系中凋亡的决定似乎是在G2检查点做出的。此外，我们鉴定了一种抗辐射的HL-60变体HCW-2。HCW-2细胞显示出与亲代HL-60细胞系相同的DNA损伤诱导和修复能力。因此，这两种细胞系之间的差异似乎在于，X射线照射可诱导HL-60细胞凋亡，但不能诱导HCW-2细胞凋亡。矛盾的是，HCW-2细胞显示出高水平的促凋亡蛋白bax表达，且不再表达抑制凋亡的bcl-2。HCW-2细胞对凋亡的抗性可能是由于获得了bcl-XL（一种与bcl-2相关的凋亡抑制剂）的表达。总之，尽管存在内源性bcl-2，但在G2检查点，X射线照射的HL-60细胞可通过p53非依赖机制诱导凋亡。HCW-2细胞所表现出的抗性表明bcl-XL可阻断这一过程。
