<i>myo</i>‐Inositol reverses Li<sup>+</sup>‐induced inhibition of phosphoinositide turnover and ornithine decarboxylase induction during early lymphocyte activation

Mustelin, Tomas; Pösö, Hannu; Iivanainen, Antti; Andersson, Leif C.

doi:10.1002/eji.1830160724

Cited by 30 publications

(11 citation statements)

References 32 publications

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“…We have earlier shown that an intact inositol metabolism is obligatory for the early activation of ODC (Mustelin et al, 1986). Here we show that the rapid ODC activation is inducible by nonhydrolysable GTP analogues, suggesting that a G-protein is an important link in the transduction of mitogenic signals.…”

Section: Introductionsupporting

confidence: 50%

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

Mustelin¹,

Pösö²,

Andersson³

1986

The EMBO Journal

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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.

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Section: Introductionsupporting

confidence: 50%

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

Mustelin¹,

Pösö²,

Andersson³

1986

The EMBO Journal

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“…We also examined the possibility that the effect of Li' on tubulin was related to its known interference with phospholipidmediated events via inhibition of myo-inositol l-phosphatase, resulting in the depletion of myo-inositol (Hallcher and Sherman, 1980;Berridge, 1984). Such effects can be mitigated by excess exogenous myo-inositol (Mustelin et al, 1986;Forer and Sillers, 1987;Busa and Gimlich, 1989). However, addition of 0.0 I -1 mM myo-inositol concurrently with Li' did not attenuate the Li+-induced decrease in radiolabeled tubulin levels.…”

Section: Resultsmentioning

confidence: 99%

Rapid Degradation of Newly Synthesized Tubulin in Lithium‐Treated Sensory Neurons

Bennett

Hollander

Laskowska

et al. 1991

Journal of Neurochemistry

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When cultured chick sensory neurons were labeled with [35S]methionine for 1 h or longer in the presence of 5-25 mM LiCl, we found a dose-dependent reduction in the level of radiolabeled tubulin, to one third of control levels, with no noticeable effect on other proteins. The magnitude of this response was identical after a 1-h or 72-h preincubation in 25 mM LiCl and returned to control values within 1 h after removal of LiCl. Short (5-min) pulse-chase experiments revealed that tubulin synthesis was not affected by Li+, but that newly synthesized tubulin was rapidly degraded, such that 50% of the labeled beta-tubulin was lost within 5 min. There was no enhanced degradation of tubulin present before exposure to Li+. Addition of LiCl at various times before and after a 10-min pulse suggested that tubulin becomes completely refractory to Li(+)-induced degradation within 10 min after translation. Although Li+ treatment resulted in a decrease in the fraction of extant tubulin present in the unassembled form, the Li(+)-induced degradation of nascent tubulin is not a consequence of shifts in assembly state, because colcemid or taxol treatment did not lead to rapid degradation of newly synthesized tubulin, and neither drug altered the response to Li+. We suggest that Li+ interferes with the correct folding of tubulin polypeptides, exposing sites, normally hidden, to the action of a protease(s).

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“…One possible mode of action is interference by Li+ with inositol lipid turnover (Berridge, 1984) due to inhibition of phosphatidylinositol resynthesis (Hallcher and Sherman, 1980). Some of these consequences can be mitigated by the addition of excess exogenous myu-inositol (Mustelin et al, 1986;Forer and Sillers, 1987;Busa and Gimlich, 1989). On the other hand, if reduction in cyclic AMP levels (Zohar et a]., (lanes 2-6).…”

Section: Inhibition Of Neurofilament-m Phosphor Yla Tionmentioning

confidence: 99%

Lithium Chloride Inhibits the Phosphorylation of Newly Synthesized Neurofilament Protein, NF‐M, in Cultured Chick Sensory Neurons

Bennett

Laskowska²,

DiLullo

1991

Journal of Neurochemistry

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The middle and high molecular weight members of the neurofilament triplet, NF-M and NF-H, undergo extensive posttranslational polyphosphorylation, a process requiring 24 h or more for completion. We have investigated ways of perturbing this process in intact cells and have found that phosphorylation of newly synthesized NF-M in cultured chick sensory neurons is inhibited by Li+. [35S]Methionine pulse-chase experiments were carried out with pure neuronal cultures, and the phosphorylation of newly synthesized NF-M was monitored by following the accompanying change, with chase time, in apparent size and charge of the polypeptide. Addition of LiCl to the medium inhibited this mobility shift in a dose-dependent manner over concentrations between 2 and 25 mM. Incorporation of 32P into NF-M, as well as NF-H, was also inhibited, whereas incorporation into the low molecular weight neurofilament protein, beta-tubulin, and total protein was unaffected. Protein synthesis was not altered. Exposure to 25 mM LiCl for up to 72 h was not toxic, and the inhibition of NF-M phosphorylation was completely reversible. When 25 mM Li+ was added after NF-M had become partially phosphorylated, further progression was blocked, but there was no net dephosphorylation or degradation of NF-M. Additional experiments suggest that this action of Li+ is probably not due to effects on second messenger levels or to effects on tubulin metabolism and assembly state presented in our accompanying article, but rather to interference by Li+ itself, with the phosphorylation of NF-M and NF-H by specific neurofilament kinase(s).

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

Cited by 30 publications

References 32 publications

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

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

Rapid Degradation of Newly Synthesized Tubulin in Lithium‐Treated Sensory Neurons

Lithium Chloride Inhibits the Phosphorylation of Newly Synthesized Neurofilament Protein, NF‐M, in Cultured Chick Sensory Neurons

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

Cited by 30 publications

References 32 publications

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

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

Rapid Degradation of Newly Synthesized Tubulin in Lithium‐Treated Sensory Neurons

Lithium Chloride Inhibits the Phosphorylation of Newly Synthesized Neurofilament Protein, NF‐M, in Cultured Chick Sensory Neurons

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