Melatonin suppresses the induction of AP-1 transcription factor components in the pars tuberalis of the pituitary

doi:10.1016/0303-7207(96)03897-X

Molecular and Cellular Endocrinology

Volume 123, Issue 1, 14 October 1996, Pages 71-80

https://doi.org/10.1016/0303-7207(96)03897-X Get rights and content

Abstract

In ovine pars tuberalis cells which express high affinity Mel 1a melatonin receptors, the ability of melatonin to directly stimulate or inhibit AP-1 transcription factor gene expression was studied. Effects of melatonin upon mRNA expression by forskolin, serum and IGF-1 were also investigated. Northern analysis showed melatonin had no direct stimulatory nor inhibitory effect upon transcription or translation. Melatonin was able to significantly inhibit forskolin-stimulated induction of c-fos and jun B mRNA whilst forskolin had no effect upon c-jun or jun D. Induction of c-Fos translation by forskolin was also inhibited by melatonin. Serum induced c-fos and c-jun, but melatonin was unable to affect these changes. Similarly IGF-1 stimulated c-fos and melatonin had no effect upon this induction. From these results it can be concluded that melatonin has no independent effects on expression of the AP-1 genes, rather its primary function is to inhibit cell activities through cyclic AMP-dependent routes of gene activation.

References (36)

P. Angel et al.
The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation
Biochim. Biophys. Acta
(1991)
M. Karin
The regulation of AP-1 activity by mitogen-activated protein kinases
J. Biol. Chem.
(1995)
P. Chomczynski et al.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Anal. Biochem.
(1987)
K.A.W. Lee et al.
A small-scale procedure for preparation of nuclear extracts that support efficient transcription and pre-mRNA splicing
Gene Anal. Tech.
(1988)
O.H. Lowry et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951)
S. McNulty et al.
Phospholipases and melatonin signal transduction in the ovine pars tuberalis
Mol. Cell. Endocrinol.
(1994)
L.F. Lau et al.
Genes induced by serum growth factors
J. Vanecek et al.
Melatonin modulates diacylglycerol and arachidonic acid metabolism in the anterior pituitary of immature rats
Neurosci. Lett.
(1990)
D.S. Carter et al.
Antigonadal effects of timed melatonin infusions in pinealectomised male Djungarian hamsters (Phodpus sungorus sungorus): duration is the critical parameter
Endocrinology
(1983)
L. Tamarkin et al.
Melatonin: a coordinating signal for mammalian reproduction
Science
(1985)

G.A. Lincoln

Effects of placing micro-implants of melatonin in the pars tuberalis, pars distalis and the lateral septum of the forebrain on the secretion of FSH and prolactin and testicular size in rams

J. Endocrinol.

(1994)

B. Malpaux et al.

The ovine pars tuberalis does not appear to be targeted by melatonin to modulate luteinizing hormone secretion, but may be important for prolactin release

J. Neuroendocrinol.

(1995)

G.A. Lincoln et al.

Photoperiodically-induced cycles in the secretion of prolactin in hypothalamo-pituitary disconnected rams: evidence for translation of the melatonin Signal in the pituitary gland

J. Neuroendocrinol.

(1994)

P.J. Morgan et al.

The ovine pars tuberalis secretes a factor which regulates gene expression in both lactotrophic and non-lactotrophic pituitary cells

Endocrinology

(1996)

P.J. Morgan et al.

Melatonin inhibits cyclic AMP production in cultured ovine pars tuberalis cells

J. Endocrinol.

(1989)

D.G. Hazlerigg et al.

Melatonin inhibits the activation of cyclic AMP-dependent protein kinase in cultured pars tuberalis cells from ovine pituitary

J. Neuroendocrinol.

(1991)

S. McNulty et al.

Melatonin regulates the phosphorylation of CREB in ovine pars tuberalis

J. Neuroendocrinol.

(1994)

D.G. Hazlerigg et al.

Regulation of mitogen-activated protein kinase in the pars tuberalis of the ovine pituitary: interactions between melatonin, insulin-like growth factor, and forskolin

Endocrinology

(1996)

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Melatonin (N-acetyl-5-methoxytryptamine) has revealed itself as an ubiquitously distributed and functionally diverse molecule. The mechanisms that control its synthesis within the pineal gland have been well characterized and the retinal and biological clock processes that modulate the circadian production of melatonin in the pineal gland are rapidly being unravelled. A feature that characterizes melatonin is the variety of mechanisms it employs to modulate the physiology and molecular biology of cells. While many of these actions are mediated by well-characterized, G-protein coupled melatonin receptors in cellular membranes, other actions of the indole seem to involve its interaction with orphan nuclear receptors and with molecules, for example calmodulin, in the cytosol. Additionally, by virtue of its ability to detoxify free radicals and related oxygen derivatives, melatonin influences the molecular physiology of cells via receptor-independent means. These uncommonly complex processes often make it difficult to determine specifically how melatonin functions to exert its obvious actions. What is apparent, however, is that the actions of melatonin contribute to improved cellular and organismal physiology. In view of this and its virtual absence of toxicity, melatonin may well find applications in both human and veterinary medicine.
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Research paperMelatonin suppresses the induction of AP-1 transcription factor components in the pars tuberalis of the pituitary

Abstract

Biochim. Biophys. Acta

J. Biol. Chem.

Anal. Biochem.

Gene Anal. Tech.

J. Biol. Chem.

Mol. Cell. Endocrinol.

Neurosci. Lett.

Antigonadal effects of timed melatonin infusions in pinealectomised male Djungarian hamsters (Phodpus sungorus sungorus): duration is the critical parameter

Endocrinology

Melatonin: a coordinating signal for mammalian reproduction

Science

Effects of placing micro-implants of melatonin in the pars tuberalis, pars distalis and the lateral septum of the forebrain on the secretion of FSH and prolactin and testicular size in rams

J. Endocrinol.

The ovine pars tuberalis does not appear to be targeted by melatonin to modulate luteinizing hormone secretion, but may be important for prolactin release

J. Neuroendocrinol.

Photoperiodically-induced cycles in the secretion of prolactin in hypothalamo-pituitary disconnected rams: evidence for translation of the melatonin Signal in the pituitary gland

J. Neuroendocrinol.

The ovine pars tuberalis secretes a factor which regulates gene expression in both lactotrophic and non-lactotrophic pituitary cells

Endocrinology

Melatonin inhibits cyclic AMP production in cultured ovine pars tuberalis cells

J. Endocrinol.

Melatonin inhibits the activation of cyclic AMP-dependent protein kinase in cultured pars tuberalis cells from ovine pituitary

J. Neuroendocrinol.

Melatonin regulates the phosphorylation of CREB in ovine pars tuberalis

J. Neuroendocrinol.

Regulation of mitogen-activated protein kinase in the pars tuberalis of the ovine pituitary: interactions between melatonin, insulin-like growth factor, and forskolin

Endocrinology

Research paper
Melatonin suppresses the induction of AP-1 transcription factor components in the pars tuberalis of the pituitary