Cellular oxidative stress and the control of apoptosis by wild-type p53, cytotoxic compounds, and cytokines.

Abstract

Apoptosis induced by wild-type p53 or cytotoxic compounds in myeloid leukemic cells can be inhibited by the cytokines interleukin 6, interleukin 3, granulocytemacrophage colony-stimulating factor, and interferon 'y and by antioxidants. The antioxidants and cytokines showed a cooperative protective effect against induction of apoptosis. Cells with a higher intrinsic level of peroxide production showed a higher sensitivity to induction of apoptosis and required a higher cytokine concentration to inhibit apoptosis. Decreasing the intrinsic oxidative stress in cells by antioxidants thus inhibited apoptosis, whereas increasing this intrinsic stress by adding H202 enhanced apoptosis. Induction of apoptosis by wild-type p53 was not preceded by increased peroxide production or lipid peroxidation and the protective effect of cytokines was not associated with a decrease in these properties. The results indicate that the intrinsic degree of oxidative stress can regulate cell susceptibility to wild-type p53-dependent and p53-independent induction of apoptosis and the ability of cytokines to protect cells against apoptosis.

Oxidant regulation of gene expression and neural tube development: Insights gained from diabetic pregnancy on molecular causes of neural tube defects

“…(It should be noted that the difference in Pax-3 mRNA between non-diabetic pregnancies that were or were not treated with α-tocopherol was neither statistically nor biologically significant, as there was no difference in the rate of NTD.) Nevertheless, because oxidative stress can activate p53-dependent apoptosis [51,52], neuroepithelium, which develops at the same time that oxidative metabolism increases, could be at particular risk for p53-dependent apoptosis. Thus, Pax-3 might be required to override p53-dependent apoptosis in order to allow neural tube formation to proceed.…”

Mn‐SOD antisense upregulates in vivo apoptosis of squamous cell carcinoma cells by anticancer drugs and γ‐rays regulating expression of the BCL‐2 family proteins, COX‐2 and p21

“…29,30 In contrast, oxidative stress by radiation, anticancer agents and postischemic reperfusions induces cell impairment and apoptosis through peroxidation of proteins and DNA and activation of the molecules in the death-signaling pathways. [31][32][33] Although the details of ROI-associated apoptotic signaling have not been clarified, the finding that ROIs reduce ⌬⌿ m and finally activate caspase-9 and caspase-3 is well known. [13][14][15]27 In addition, ROIs activate kinases associated with apoptosis.…”

Cytokine control of developmental programs in normal hematopoiesis and leukemia

“…We found that expression of the tumor suppressor wild-type p53 is an important physiological signal for activation of apoptosis (Yonish-Rouach et al, 1991). Overexpression of wild-type p53 is su cient to induce apoptosis in myeloid leukemic cells (Yonish-Rouach et al, 1991;Lotem and Sachs, 1995a, 1996aLotem et al, 1996) and other cell types (Shaw et al, 1992;Abrahamson et al, 1995). The use of p53 de®cient mice has shown that wild-type p53 is required for induction of apoptosis in normal in vitro colony forming cells by g-irradiation (Lotem and Sachs, 1993a) and in thymocytes by g-irradiation and certain DNA-damaging compounds (Lotem and Sachs, 1993a;Clarke et al, 1993;Lowe et al, 1993).…”

“…Cytokines also suppressed induction of apoptosis in cytokine independent myeloid leukemic cells by transforming growth factor b1 (Lotem and Sachs, 1992b), and by overexpression of wild-type p53 in myeloid leukemic (Yonish-Rouach et al, 1991;Lotem and Sachs, 1995a, 1996a,b, 1997Lotem et al, 1996) and erythroleukemic cells (Abrahamson et al, 1995). IL-3 and GM-CSF suppressed induction of apoptosis by the chemotherapeutic compound doxorubicin in primary cultures of human myeloid leukemia cells (Kaplinsky et al, 1996) and IL-3 suppressed girradiation induced apoptosis in normal myeloid hematopoietic cells and IL-3 dependent cell lines (Collins et al, 1992;Canman et al, 1995).…”