Nerve growth factor in the anterior pituitary: localization in mammotroph cells and cosecretion with prolactin by a dopamine-regulated mechanism.

Missale, Cristina; Boroni, F.; Sigala, Sandra; Buriani, Alessandro; Fabris, Michele; Leon, Alberta; Toso, Roberto Dal; Spano, PierFranco

doi:10.1073/pnas.93.9.4240

Cited by 74 publications

(42 citation statements)

References 56 publications

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“…Trk effects may be mediated by PLC-␥-and IP-3-induced release of calcium from intracellular stores (54,55), consistent with the recent report that chelators of intracellular, but not extracellular, calcium blocked neurotrophin-induced neurotrophin secretion (21). Indirect mechanisms also may be at work; for example, neurotrophins may trigger neurotransmitter release, which in turn causes depolarization and neurotrophin release (56). The specific signal transduction mechanisms used in neurons may depend not only on the cellular context, but on the subcellular location of the released neurotrophins and activated receptors as well.…”

Section: Figsupporting

confidence: 66%

Neurotrophins induce release of neurotrophins by the regulated secretory pathway

Krüttgen

Heymach

Shooter

1998

Proc. Natl. Acad. Sci. U.S.A.

113

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Recent studies have established that neurotrophin synthesis and secretion are regulated by activity and that these factors are involved in activity-dependent processes in the nervous system. Neurotrophins also are known to induce increases in intracellular calcium, a trigger for regulated secretion. This finding raises the possibility that neurotrophins themselves may stimulate regulated secretion of neurotrophins. To address this question, we studied the release of neurotrophins from transfected PC12 cells, a widely used model for neuronal secretion and neurotrophin signal transduction. We found that neurotrophins induced the regulated secretion of brain-derived neurotrophic factor, neurotrophin-3 (NT-3), and neurotrophin-4/5. The effect of brain-derived neurotrophic factor on release of NT-3 could be abolished by REX, a p75 blocking antibody, but not by K252a, an inhibitor of neurotrophin tyrosine kinase receptor (Trk) signaling. The nerve growth factor effect on release of NT-3 could be blocked only by simultaneous application of REX and K252a, suggesting that they are mediated by TrkA as well as p75. Our data show that neurotrophins are able to induce the regulated secretion of neurotrophins and suggest a signal-transducing role for both TrkA and p75 in this process. The neurotrophin-induced release of neurotrophins may be relevant for activity-dependent processes such as synaptic plasticity and memory formation.

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Section: Figsupporting

confidence: 66%

Neurotrophins induce release of neurotrophins by the regulated secretory pathway

Krüttgen

Heymach

Shooter

1998

Proc. Natl. Acad. Sci. U.S.A.

113

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“…In particular, NGF has been consistently reported to induce differentiation of the pituitary tumor cell line GH 3 (15) and the insulinoma cell line RINm5F (16,17) and to suppress cell growth and tumorigenicity of human prolactin-secreting adenomas (18,19). In addition, we found that an autocrine loop mediated by NGF is operative in both normal pituitary lactotroph cells (20) and slowly proliferating, nontumorigenic prolactinomas but not in tumorigenic prolactinoma cells (18,21). The impact of this mechanism is such that the breakdown of the NGF-mediated autocrine loop in nontumorigenic prolactinomas brings about their neoplastic progression to a tumorigenic phenotype (21).…”

mentioning

confidence: 53%

Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines

Missale

Codignola

Sigala

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Nerve growth factor (NGF) has antiproliferative and differentiating effects on adenomas of neuroendocrine origin. Cell lines derived from small-cell lung carcinoma (SCLC), a very aggressive neuroendocrine tumor, express NGF receptors. The role of NGF in the control of proliferation and progression of this carcinoma, however, has never been investigated. Chronic exposure of NCI-N-592 and GLC8 SCLC cell lines to NGF remarkably inhibited their proliferation rate both in vitro and in vivo, prevented their anchorage-independent clonal growth in soft agar, impaired their invasive capacity in vitro, and abolished their tumorigenic potential in nude mice. The proliferative response of SCLC cell lines to nicotine was also remarkably impaired by in vitro NGF treatment. Furthermore, NGF treatment activates in SCLC cell lines the expression and secretion of NGF. NGF thus reverts SCLC cell lines to a noninvasive, nontumorigenic phenotype that does not respond to nicotine and produces NGF.Small-cell lung cancer (SCLC) is a very aggressive human tumor representing about 25% of all lung cancers (1). Although our understanding of the biology of SCLC is expanding rapidly, there have been no recent major advances in the treatment of this tumor, and overall survival has not changed significantly since the late 1970s (1). SCLC has some phenotypical properties of a neuroendocrine tumor such as expression of L-dopa decarboxylase (1, 2), bombesin͞gastrin-releasing peptide (1, 3), neuron-specific enolase (1), and voltage-operated calcium channels of neuronal type (4-6). Proliferation of SCLC is controlled by autocrine loops sustained by the secretion of different neurohormones and growth factors such as bombesin, insulin-like growth factor I, bradykinin, neurotensin, cholecystokinin, and vasopressin (1). A mitogenic loop mediated by serotonin (5-HT) and facilitated by neuronal-type nicotinic receptors through stimulation of 5-HT release (7, 8) has been recently shown to be operative in SCLC cell lines (9, 10).Despite the observation that SCLC cell lines express (11) the tyrosine kinase trkA receptor for NGF (12)(13)(14), the role of this neurotrophin in the control of proliferation, invasiveness, and tumorigenic potential of this tumor has never been investigated. This issue seems of critical relevance as it is now emerging that NGF is an antiproliferative and differentiation factor for various tumors of neuroendocrine origin (15-21). In particular, NGF has been consistently reported to induce differentiation of the pituitary tumor cell line GH 3 (15) and the insulinoma cell line RINm5F (16,17) and to suppress cell growth and tumorigenicity of human prolactin-secreting adenomas (18,19). In addition, we found that an autocrine loop mediated by NGF is operative in both normal pituitary lactotroph cells (20) and slowly proliferating, nontumorigenic prolactinomas but not in tumorigenic prolactinoma cells (18,21). The impact of this mechanism is such that the breakdown of the NGF-mediated autocrine loop in nontumorigenic prolactinoma...

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“…NGF and Trk receptors have been identified in endocrine cells (cells containing conventional anterior-pituitary hormones) in the anterior pituitary of adult rats [8,15,16,17,18]. Both NGF and its receptor p75 NTR have been detected in a distinct population of cells in adult primate anterior pituitary [19].…”

Section: Introductionmentioning

confidence: 99%

“…Animal studies have shown that neurotrophins, particularly NGF, play a dual role in pituitary physiology: a local one, in the anterior pituitary, as a stimulator of differentiation and proliferation of lactotrope cells during development [7] and a systemic one as a neurohormone which is co-secreted with prolactin into the bloodstream [8, 9]. Furthermore, NGF may regulate endocrine function by stimulating the hypothalamo-pituitary-adrenocortical axis activity during stress responses [10].…”

Section: Introductionmentioning

confidence: 99%

p75<sup>NTR</sup> and TrkC Neurotrophin Receptors Demonstrate a Different Immunoreactivity Profile in Comparison to TrkA and TrkB Receptors in Human Normal Pituitary Gland and Adenomas

Assimakopoulou¹,

Zolota²,

Chondrogianni³

et al. 2008

Neuroendocrinology

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Background/Aims: Recent knowledge indicates that neurotrophins play a significant role in neuroendocrine systems through their specific receptors TrkA, TrkB, TrkC and low-affinity p75^NTR receptor. TrkA and TrkB receptors have been previously detected in numerous endocrine cells in human anterior pituitary and adenomas. In the present study, the localization of p75^NTR and TrkC along with TrkA and TrkB receptors was investigated. Methods: Semi-serial paraffin-embedded sections of 5 human normal pituitaries and 30 adenomas were immunostained using specific antibodies. Results: Expression of p75^NTR receptor was demonstrated in the intricate capillary and reticulin network in the anterior pituitary and in the pericapillary tissue and pituicytes in the posterior lobe. p75^NTR immunoreactivity was absent from all adenomas. In normal anterior pituitary, a few scattered cells showed weak TrkC immunoreactivity in contrast to a high percentage of endocrine cells distributed throughout the pars distalis and pars intermedia which exhibited strong TrkA and/or intermediate TrkB immunoreactivity. Double immunohistochemistry demonstrated TrkA immunoreactivity in more than 80% of lactotropes and 70% of corticotropes and to a lesser extent in other cell types. Furthermore, in the majority of adenomas, independently of type, sex and age, a high percentage of TrkA- and/or TrkB-positive cells was detected. Interestingly, TrkC expression appeared to be increased in some adenomas compared to normal pituitary. Endothelial cells and perivascular connective tissue were always TrkB-immunostained. Conclusion: The above findings support a potential role of all neurotrophins, through their different receptors, in pituitary functions.

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Nerve growth factor in the anterior pituitary: localization in mammotroph cells and cosecretion with prolactin by a dopamine-regulated mechanism.

Cited by 74 publications

References 56 publications

Neurotrophins induce release of neurotrophins by the regulated secretory pathway

Neurotrophins induce release of neurotrophins by the regulated secretory pathway

Nerve growth factor abrogates the tumorigenicity of human small cell lung cancer cell lines

p75<sup>NTR</sup> and TrkC Neurotrophin Receptors Demonstrate a Different Immunoreactivity Profile in Comparison to TrkA and TrkB Receptors in Human Normal Pituitary Gland and Adenomas

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