Biomedical subjects

T Mustelin

Publications and source records attributed to T Mustelin.

76 records · Page 5Linked to original sources

PubMed1987

GTP dependence of the transduction of mitogenic signals through the T3 complex in T lymphocytes indicates the involvement of a G-protein.

The T3 molecule on the surface membrane of T lymphocytes is involved in the transduction of the proliferation signal generated by an interaction between the antigen receptor and an antigen, to the interior of the T cell. Mitogenic monoclonal antibodies against the T3 molecule and mitogenic lectins induce a rapid (within 5 min) protein synthesis-independent activation of ornithine decarboxylase (ODC) in human T lymphocytes. When T cells are selectively depleted of guanine nucleotides by treatment with mycophenolic acid, the early mitogen-induced activation of ODC is completely inhibited. The inhibition rapidly reverted on the addition of guanine a few minutes before the mitogenic stimulation, and even more rapidly by GTP directly introduced into the T cells by a transient membrane permeabilization. GTP can be substituted for by a non-hydrolyzable GTP analogue, GTP-gamma-S, which also induces ODC activity by itself in human T cells. These results suggest that a G-protein(s) is involved in the transduction of the proliferation signal in human T cells.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1987

Transduction of mitogenic signals in T lymphocytes. Role of inositol phospholipids for the rapid activation of ornithine decarboxylase.

Treatment of human T lymphocytes with mitogenic ligands, such as concanavalin A (Con A), induces a rapid activation of the enzyme ornithine decarboxylase (ODC). This activation occurs within minutes and is completely inhibited when the cells are treated with 1 mM Li+ (in an inositol-free medium) prior to stimulation with Con A. In the presence of 1 mM myo-inositol Li+ has no effect on the Con A-induced activation of ODC. To elucidate why inositol is needed for the mitogen-induced activation of ODC in T lymphocytes, we tested the ability of different inositol metabolites to reverse the inhibitory effect of Li+. Here we report that inositol phospholipids, in addition to inositol, reverse the Li+-induced inhibition of ODC activation, while all other inositol derivatives tested were ineffective. This indicates that Li+ does not block the activation of ODC by inhibiting the generation of inositol phosphates, but rather by a mechanism which is circumvented if inositol phospholipids are added. The molecular mechanisms involved in the rapid activation of ODC by mitogens in human T lymphocytes apparently require inositol phospholipids, but are not directly mediated by inositol-1,4,5-trisphosphate (IP3) alone, diacylglycerol alone, or other inositol phosphates.

Enzyme Activation↗

PubMed1986

Role of G-proteins in T cell activation: non-hydrolysable GTP analogues induce early ornithine decarboxylase activity in human T lymphocytes.

Rapid activation of ornithine decarboxylase is one of the earliest recognized events during induction of a mitogenic response in human T lymphocytes. Here we show that the non-hydrolysable GTP analogues guanine-5-(gamma-thio)trisphosphate and guanylyl-5-imidodiphosphate, introduced into human T cells by means of a transient membrane permeabilization technique, can replace an external mitogenic ligand, such as concanavalin A, in inducing early ornithine decarboxylase activity. Neomycin inhibits this rapid activation at concentrations known to bind to phosphoinositides. One of the two compounds formed in polyphosphoinositide breakdown, inositol-1,4,5-trisphosphate, also induces ornithine decarboxylase activity. The other, diacylglycerol, apparently does not, since the phorbol ester, tetradecanoyl phorbol acetate, which is thought to mimic the action of diacylglycerols, does not alter basal ornithine decarboxylase activity in T cells until several hours after administration. These findings indicate that guanine nucleotide-binding regulatory (G-) protein(s) participates in the transduction of the mitogenic signal. The intracellular target system for this G-protein may include phosphoinositide breakdown and generation of inositoltrisphosphate, which might be involved in the early activation of ornithine decarboxylase.

Cell Membrane Permeability↗

PubMed1986

myo-Inositol reverses Li+-induced inhibition of phosphoinositide turnover and ornithine decarboxylase induction during early lymphocyte activation.

One of the earliest detectable responses by T lymphocytes in vitro to various mitogenic ligands is the rapid induction of ornithine decarboxylase (ODC) activity (Scott et al., Eur. J. Immunol. 1985. 15: 783). This early activation is measurable within minutes after the addition of the mitogen. The T cell mitogen concanavalin A also induces rapid breakdown of phosphoinositides in T lymphocytes. The inositol phosphates formed are recycled and used in synthesis of new phosphoinositides. Li+ interrupts this cycle by inhibiting the enzyme inositol-1-phosphatase, which produces the inositol needed for phosphoinositide synthesis. Here we report that when human blood lymphocytes are kept in an inositol-deficient medium for 30 min in the presence of 1 mM Li+, the cells become unable to respond to mitogens by inositide breakdown and rapid induction of ODC activity. Addition of 1 mM myo-inositol restores the inducibility of these responses within a few minutes. These findings represent a novel aspect of the activation of resting lymphocytes and implies a new role for the inositol turnover during signal transduction.

Chlorides↗