Nitric oxide modulation of human leukemia cell differentiation and gene expression

Abstract

Nitric oxide (NO) functions as an intercellular messenger molecule in such varied contexts as neurotransmission, immune regulation, and the control of vascular tone. We report that NO, delivered as purified gas or released from the pharmacologic NO donors sodium nitroprusside or 6- morpholino-sydnonimine, caused monocytic differentiation of cells of the human myeloid leukemia cell line HL-60 and altered gene expression. The treated cells stopped proliferating, became spread and vacuolated, had increased expression of nonspecific esterase and the monocyte marker CD14, and displayed increased capacity to produce hydrogen peroxide. Furthermore, these treated cells had increased steady-state expression of messenger RNA (mRNA) for tumor necrosis factor-alpha (TNF- alpha) and interleukin-1 beta (IL-1 beta), but decreased expression of mRNA for the proto-oncogenes c-myc and c-myb. The increase in TNF-alpha and IL-1 beta mRNA levels was due (at least in part) to a new transcription of these specific mRNAs. NO elaborated in the bone marrow microenvironment may have a role in normal and malignant hematopoietic cell growth and differentiation.

Biosynthesis of nitric oxide activates iron regulatory factor in macrophages.

“…In conclusion, our results have far-reaching implications as they disclose that endogenously produced NO, besides altering the activity of iron-dependent enzymes posttranslationally, can also modulate gene expression. This idea is supported by recent findings indicating that NO, as gas or released from NO donors, modulates cytokine and oncogene mRNA levels in a myelomonocytic cell line (Magrinat et al, 1992) and activates the transciption factor NF-xB in human monocytes (Lander et al, 1993). At this juncture, it is tempting to speculate that other trans-regulators that may contain iron or sulfhydryl groups, essential for binding activity, represent a potential target for endogenous NO.…”

Nitric oxide and cGMP analogs activate transcription from AP‐1‐responsive promoters in mammalian cells

“…Nitric oxide (NO) is an important signal transducer in many cells and tissues including blood vessels, neuronal cells, and hematopoietic cells (2). NO has been implicated in the regulation of many biological processes, including smooth muscle relaxation, neurotransmission, inhibition of platelet aggregation, immune regulation, and cellular differentiation (3,4). NO produces its effects through a variety of mechanisms including nitrosylation of (or redox reactions with) metal-and thiol-containing proteins (5).…”

“…Although the number of newly discovered potential targets of NO continues to increase, the effect of NO in many systems appears to be mediated principally through the stimulation of cytosolic guanylate cyclase, a heme-contaming enzyme; in these systems the effects of NO can be at least partially mimicked by membrane-permeable cGMP analogs (2,4). In hematopoietic cells, NO-releasing agents and cGMP analogs change expression of differentiation-associated genes and induce cellular differentiation (3,6…”

Inactivation of glutathione peroxidase by nitric oxide leads to the accumulation of H2O2and the induction of HB‐EGF via c‐Jun NH2‐terminal kinase in rat aortic smooth muscle cells

“…These findings indicate that the induction of HB-EGF by NO would be an adaptive response as an autocrine protective factor against apoptosis by NO in RASMCs.Key words: gluthathione peroxidase • nitric oxide • JNK • HB-EGF • apoptosis itric oxide (NO) serves as an important signal transducer in several cells and tissues, including blood vessels and neuronal and hematopoietic cells (1, 2). It is generally thought that NO is involved in the regulation of a wide variety of biological processes, including smooth muscle relaxation, neurotransmission, inhibition of platelet aggregation, immune regulation, and cellular differentiation (3,4). NO functions via a variety of mechanisms, including nitrosylation of (or redox reactions with) metal-and thiol-containing proteins (5).…”