TNFα‐induced aerobic synthesis of ATP on plasma membranes of target cells. The relation to the expression of the nuclear oncogene c‐myc

Abstract

The accumulation of ATP by preparations of plasma membranes enriched particles (PMEP) isolated from rat hepatocytes, murine splenocytes and human T-lymphocytes has been investigated after the binding of human and murine tumour necrosis factors (TNFct) to their specific receptors. The TNFc~-induced expression of the nuclear oncogene c-myc in intact hepatocytes has been also studied. TNFc~ induced the marked biosynthesis of ATP on PMEP of hepatocytes and splenocytes within the first minute of incubation. The biosynthesis of ATP was independent of the activity of adenylate kinase and only occured in the presence of all the components of aerobic phosphorylation and the electron acceptor, cytochrome C or diferric transferrin. The level of ATP on PM correlated with the degree of expression of the nuclear oncogene c-myc in the same target cells. Adriamycin totally suppressed the biosynthesis of ATP on PM and simultaneously inhibited the expression of c-myc. The ATP synthesized on PM is suggested to be involved in transduction of the proliferative or growth signal to the cell nucleus.

Plasma membrane signal-transducing ATP

“…These experiments were carried out on PMEP isolated from human T lymphocytes. It was shown that the presence of only ADP (the substrate for adenylate cyclase) in the medium is insufficient for ATP biosynthesis on the plasma membrane, on the other hand, the presence of W,PS-di(adenosine-5')pentaphosphate in the incubation medium in concentrations suppressing adenylate cyclase did not inhibit ATP biosynthesis on the plasma membrane stimulated by tumor necrosis factors (TNF) [28].…”

“…Studies of TNF<t showed that ATP synthesis induced in plasma membranes of mouse splenocytes and rat hepatocytes was completely inhibited with amiloride (Na+/H + exchange inhibitor and blocker of Na + influx) and the antitumor antibiotic adriamycin [28].…”

“…Blockade of ATP synthesis with the antitumor antibiotic adriamycin was accompanied by 0.5-2-h blockade ofc-myc expression. Therefore, ATP synthesized on the plasma membrane can participate in the transduction of the proliferative signal into the cell nucleus [28].…”

“…Electron acceptors are essential for ATP synthesis, and ATP is not formed without electron carriers, while substitution of cytochrome C for iron-containing acceptor (ferritin transferrin) typical of the outer plasma membrane [42] had no effects on ATP biosynthesis [28].…”

Modulation of GdCl3and Angelica Sinensis polysaccharides on differentially expressed genes in liver of hepatic immunological injury mice by cDNA microarray

“…TNF alpha can cause liver cell apoptosis through the TNF-alpha receptor or Fas/CD95, which is expressed by liver cells. The TNF-alpha induced expression of the nuclear oncogene c-myc in intact hepatocytes has been studied [28] . The expression of Hsmycl is down-regulation, which may be the reason of preventing hepatic cell from apoptosis.…”