scholarly journals Evidence of cellular senescence during the development of estrogen-induced pituitary tumors

2015 ◽  
Vol 22 (3) ◽  
pp. 299-317 ◽  
Author(s):  
Maria Eugenia Sabatino ◽  
Juan Pablo Petiti ◽  
Liliana del Valle Sosa ◽  
Pablo Anibal Pérez ◽  
Silvina Gutiérrez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Pituitary Adenomas ◽  
Pituitary Tumors ◽  
Male Rats ◽  
Pituitary Cells ◽  
Dna Damage Signaling ◽  
Estrogen Exposure ◽  
Benign Nature

Although pituitary adenomas represent 25% of intracranial tumors, they are usually benign, with the mechanisms by which these tumors usually avoid an invasive profile and metastatic growth development still remaining unclear. In this context, cellular senescence might constitute a plausible explanation for the benign nature of pituitary adenomas. In this study, we investigated the emergence of cellular senescence as a growth control mechanism during the progression of estrogen-induced pituitary tumors. The quantification of Ki67-immunopositive cells in the pituitaries of estrogenized male rats after 10, 20, 40, and 60 days revealed that the mitogenic potential rate was not sustained for the whole period analyzed and successively decreased after 10 days of estrogen exposure. In addition, the expression of cellular senescence features, such as the progressive rise in the enzymatic senescence-associated b-galactosidase (SA-b-gal) activity, IL6, IL1b, and TGFb expression, was observed throughout pituitary tumor development. Furthermore, tumoral pituitary cells also displayed nuclear pATM expression, indicating activated DNA damage signaling, with a significant increase in p21 expression also being detected. The associations among DNA damage signaling activation, SA-b-gal expression, and p21 may provide a reliable combination of senescence-associated markers for in vivo pituitary senescence detection. These results suggest a role for this cellular process in the regulation of pituitary cell growth. Thus, cellular senescence should be conceived as a contributing component to the benign nature of pituitary adenomas, thereby influencing the capability of the pituitary gland to avoid unregulated cell proliferation.

Effects of in vivo gonadal hormone environment on in vitro hGRF-40-stimulated GH release

1985 ◽  
Vol 249 (3) ◽  
pp. E276-E280 ◽  
Author(s):  
W. S. Evans ◽  
R. J. Krieg ◽  
E. R. Limber ◽  
D. L. Kaiser ◽  
M. O. Thorner
Keyword(s):  
Female Rats ◽  
Male Rats ◽  
Gonadal Hormone ◽  
Base Line ◽  
Pituitary Cells ◽  
Intact Male ◽  
Castrate Male ◽  
Basal Release

The effects of gender and the gonadal hormone environment on basal and stimulated growth hormone (GH) release by dispersed and continuously perifused rat anterior pituitary cells were examined. Cells from intact male and diestrus day 2 female rats and from castrate male rats either untreated or treated with testosterone (T) or 17 beta-estradiol (E2) were used. Basal GH release (ng/min per 10(7) cells; mean +/- SE) by cells from diestrus day 2 female rats was less than by cells from castrate rats treated with T (4.3 +/- 0.6 vs. 11.4 +/- 2.7, respectively; P less than 0.025). No other differences in basal release were detected. Concentration-response relationships were documented between human GH-releasing factor 40 (hGRF-40; 0.03-100 nM given as 2.5-min pulses every 27.5 min) and GH release. Mean (+/- SE) overall GH release (ng/min per 10(7) cells) above base line was greater by cells from intact male rats (496 +/- 92) than by cells from castrate (203 +/- 37.3; P less than 0.0001), castrate and T-treated (348 +/- 52.8; P = 0.008), or castrate and E2-treated (58.1 +/- 6.8; P less than 0.001) male rats or by diestrus day 2 rats (68.6 +/- 9.5; P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Obestatin Partially Affects Ghrelin Stimulation of Food Intake and Growth Hormone Secretion in Rodents

Endocrinology ◽  
2007 ◽  
Vol 148 (4) ◽  
pp. 1648-1653 ◽  
Author(s):  
Philippe Zizzari ◽  
Romaine Longchamps ◽  
Jacques Epelbaum ◽  
Marie Thérèse Bluet-Pajot
Keyword(s):  
Food Intake ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Male Rats ◽  
Pituitary Cells ◽  
Gh Secretion ◽  
Freely Moving ◽  
Stimulation Of

Administration of ghrelin, an endogenous ligand for the GH secretagogue receptor 1a (GHSR 1a), induces potent stimulating effects on GH secretion and food intake. However, more than 7 yr after its discovery, the role of endogenous ghrelin remains elusive. Recently, a second peptide, obestatin, also generated from proteolytic cleavage of preproghrelin has been identified. This peptide inhibits food intake and gastrointestinal motility but does not modify in vitro GH release from pituitary cells. In this study, we have reinvestigated obestatin functions by measuring plasma ghrelin and obestatin levels in a period of spontaneous feeding in ad libitum-fed and 24-h fasted mice. Whereas fasting resulted in elevated ghrelin levels, obestatin levels were significantly reduced. Exogenous obestatin per se did not modify food intake in fasted and fed mice. However, it inhibited ghrelin orexigenic effect that were evident in fed mice only. The effects of obestatin on GH secretion were monitored in superfused pituitary explants and in freely moving rats. Obestatin was only effective in vivo to inhibit ghrelin stimulation of GH levels. Finally, the relationship between octanoylated ghrelin, obestatin, and GH secretions was evaluated by iterative blood sampling every 20 min during 6 h in freely moving adult male rats. The half-life of exogenous obestatin (10 μg iv) in plasma was about 22 min. Plasma obestatin levels exhibited an ultradian pulsatility with a frequency slightly lower than octanoylated ghrelin and GH. Ghrelin and obestatin levels were not strictly correlated. In conclusion, these results show that obestatin, like ghrelin, is secreted in a pulsatile manner and that in some conditions; obestatin can modulate exogenous ghrelin action. It remains to be determined whether obestatin modulates endogenous ghrelin actions.

scholarly journals MICRORNA REGULATORS OF THE SENESCENCE TRANSCRIPTOME

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S835-S835
Author(s):  
O’Wayne Rodney ◽  
Myriam Gorospe ◽  
Kotb Abdelmohsen
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Growth Arrest ◽  
Proliferating Cells ◽  
Telomere Shortening ◽  
Qpcr Analysis ◽  
Oncogene Activation ◽  
Dna Foci ◽  
Transcriptome Signature

Abstract Cellular senescence is a state of indefinite growth arrest triggered in response to sublethal stresses such as telomere shortening, DNA damage, oxidative injury, oncogene activation, and hypoxia. Compared with proliferating cells, senescent cells are enlarged, display heterochromatic DNA foci, and express distinct subsets of proteins, including the enzyme β-galactosidase (β-gal). Previously, we identified transcriptome signature of senescent cells. We asked if these transcripts might be regulated by microRNAs (miRNAs). To address this question, we identified six miRNAs (miR-129-5p, -19a-3p, -128-3p, -124-3p, -340-5p, and -27b-3p) as potential regulators of subsets of transcripts differentially expressed during senescence. RT-qPCR analysis indicated that miR-129-5p, -19a-3p, -128-3p, -124-3p, and -340-5p were downregulated in senescent cells. We modulated these miRNAs in proliferating WI-38 fibroblasts and found that miRNA antagomirs did not show significant changes in β-gal activity. Interestingly, however, overexpression of miR-124-3p or miR-340-5p increased β-gal activity. We conclude that despite the decrease of miR-124-3p and miR-340-5p in senescent cells, their overexpression enhanced senescence as indicated by β-gal activity. Future analyses will focus on the mechanisms through which these miRNAs induce senescence and their physiologic and pathologic impacts in vivo.

scholarly journals Novel chimeric somatostatin analogs: facts and perspectives

2007 ◽  
Vol 156 (suppl_1) ◽  
pp. S23-S28 ◽  
Author(s):  
Diego Ferone ◽  
Alexandru Saveanu ◽  
Michael D Culler ◽  
Marica Arvigo ◽  
Alberto Rebora ◽  
...  
Keyword(s):  
Human Cell ◽  
Pituitary Adenomas ◽  
Somatostatin Receptor ◽  
Somatostatin Analogs ◽  
Pituitary Tumors ◽  
Receptor Activation ◽  
Specific Cell ◽  
Pituitary Cells ◽  
Dopaminergic Drugs ◽  
Cell Functions

Dopamine and somatostatin receptor agonists inhibit hormone secretion by normal pituitary cells and pituitary adenomas. Indeed, initially several dopaminergic drugs, and lately somatostatin analogs, have been developed for the treatment of pituitary adenomas. Recently, it has been demonstrated that subtypes of somatostatin and dopamine receptors may form homo- and hetero-dimers at the membrane level, as part of their normal trafficking and function. Interestingly, a specific ligand for a given receptor may influence the activity of an apparently unrelated receptor, and the association between the two different receptors could be induced by addition of either dopamine or somatostatin. The new properties of these families of G-protein coupled receptors (GPCRs) offer a potential explanation for the apparent conflicting results observed both in vivo and in vitro in human cell systems treated with the presently available analogs. Moreover, this observation not only increases the possibilities of modulating the activities of these receptors, but also raises new questions on the role of associations of specific receptors in the control of cell functions. In fact, results from preclinical studies have shown that receptor activation may not only trigger different intracellular signaling pathways, but also induce a distinct response depending upon the specific cell type. Recently, a number of new interesting compounds (subtype selective analogs and antagonists, as well as bi-specific and hybrid somatostatin/dopamine compounds) have been developed. The effects of these new molecules have been explored in few animal and human cell lines and primary cultures from human tumors, revealing a heterogeneous, but broader, profile of activities. Further studies are certainly needed to fully elucidate the complex interplay between the GPCRs and consequent biological effects, to identify suitable therapies for controlling hormonal secretion of pituitary tumors. However, these recent observations form the basis for the application of new interesting strategies for the treatment of not only pituitary tumors but also other human malignancies.

scholarly journals Inhibition of DNA damage response at telomeres improves the detrimental phenotypes of Hutchinson–Gilford Progeria Syndrome

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Julio Aguado ◽  
Agustin Sola-Carvajal ◽  
Valeria Cancila ◽  
Gwladys Revêchon ◽  
Peh Fern Ong ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Genetic Disorder ◽  
Premature Aging ◽  
Telomere Dysfunction ◽  
Damage Response ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

AbstractHutchinson–Gilford progeria syndrome (HGPS) is a genetic disorder characterized by premature aging features. Cells from HGPS patients express progerin, a truncated form of Lamin A, which perturbs cellular homeostasis leading to nuclear shape alterations, genome instability, heterochromatin loss, telomere dysfunction and premature entry into cellular senescence. Recently, we reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which control the DNA damage response (DDR) at dysfunctional telomeres. Here we show that progerin-induced telomere dysfunction induces the transcription of tncRNAs. Their functional inhibition by sequence-specific telomeric antisense oligonucleotides (tASOs) prevents full DDR activation and premature cellular senescence in various HGPS cell systems, including HGPS patient fibroblasts. We also show in vivo that tASO treatment significantly enhances skin homeostasis and lifespan in a transgenic HGPS mouse model. In summary, our results demonstrate an important role for telomeric DDR activation in HGPS progeroid detrimental phenotypes in vitro and in vivo.

scholarly journals TAMI-20. POLY(ADP-RIBOSE) GLYCOHYDROLASE INHIBITION SEQUESTERS NAD+ TO POTENTIATE THE METABOLIC LETHALITY OF ALKYLATING CHEMOTHERAPY IN IDH MUTANT TUMOR CELLS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii217-ii217
Author(s):  
Hiroaki Nagashima ◽  
Christine Lee ◽  
Kensuke Tateishi ◽  
Fumi Higuchi ◽  
Megha Subramanian ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Alkylating Agents ◽  
Metabolic Stress ◽  
Therapeutic Benefit ◽  
Dna Damage Signaling ◽  
Dna Damaging Agents ◽  
Mutant Lines ◽  
Nad Depletion

Abstract Mutations in IDH1 or IDH2 characterize the majority of diffuse infiltrative gliomas of younger adulthood. DNA alkylator chemotherapy has proven to be an effective treatment for IDH mutant glioma, yet recurrences remain frequent and improved treatments are needed. Upon exposure of cancer cells to DNA alkylating agents, poly(ADP-ribose) polymerases (PARPs) catalyze the transient oligomerization of nicotinamide adenine dinucleotide (NAD+) into poly-ADP-ribose (PAR) chain-assemblies, which stimulate the DNA damage response. Here, we find that, in IDH mutant glioma cells, alkylator-induced cytotoxicity is dramatically augmented by pharmacologic inhibition or genetic knockout of the PAR breakdown enzyme poly(ADP-ribose) glycohydrolase (PARG). Mechanistically, we show this augmentation is driven by a metabolic state pairing amplified alkylator-induced DNA damage with catastrophic depletion of NAD+. IDH mutant cancer cells have low basal levels of NAD+, rendering them vulnerable to prolonged NAD+ depletion. Either of two clinically-utilized monofunctional alkylators, procarbazine (PCZ) or temozolomide (TMZ), when exposed to multiple IDH mutant lines, activated PARP conversion of cellular NAD+ monomers into polymerized PAR. Subsequent PAR breakdown and recycling of NAD+ monomers was then halted by concomitant PARG inactivation, amplifying PARylation-mediated DNA damage signaling and critically depleting free NAD+, resulting in profound cytotoxicity. This effect was partially reversed by NAD+ rescue supplementation, confirming the key contribution of metabolic stress. Combined alkylator treatment and PARG inhibition in vivo maximized both NAD+ depletion and cytotoxicity in an endogenous IDH mutant cancer model. Thus, alkyating DNA damaging agents expose a metabolic liability in IDH mutant cancers, and subsequent targeted blockade of PAR breakdown and NAD+ metabolite recovery can exploit this vulnerability to provide genotype-specific therapeutic benefit.

scholarly journals SETD1A protects HSCs from activation-induced functional decline in vivo

Blood ◽  
2018 ◽  
Vol 131 (12) ◽  
pp. 1311-1324 ◽  
Author(s):  
Kathrin Arndt ◽  
Andrea Kranz ◽  
Juliane Fohgrub ◽  
Adrien Jolly ◽  
Anita S. Bledau ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dna Damage ◽  
Functional Decline ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Reactive Oxygen Species Accumulation ◽  
Dna Damage Signaling ◽  
Key Points

Key Points SETD1A regulates DNA damage signaling and repair in HSCs and hematopoietic precursors in the absence of reactive oxygen species accumulation. SETD1A is important for the survival of mice after inflammation-induced HSC activation in situ.

scholarly journals The DNA Damage Signaling Pathway Connects Oncogenic Stress to Cellular Senescence

Cell Cycle ◽  
2007 ◽  
Vol 6 (15) ◽  
pp. 1831-1836 ◽  
Author(s):  
Frédérick A. Mallette ◽  
Gerardo Ferbeyre
Keyword(s):  
Dna Damage ◽  
Signaling Pathway ◽  
Cellular Senescence ◽  
Dna Damage Signaling ◽  
Oncogenic Stress

scholarly journals Magmas, a Gene Newly Identified as Overexpressed in Human and Mouse ACTH-Secreting Pituitary Adenomas, Protects Pituitary Cells from Apoptotic Stimuli

Endocrinology ◽  
2010 ◽  
Vol 151 (10) ◽  
pp. 4635-4642 ◽  
Author(s):  
Federico Tagliati ◽  
Erica Gentilin ◽  
Mattia Buratto ◽  
Daniela Molè ◽  
Ettore Ciro degli Uberti ◽  
...  
Keyword(s):  
Pituitary Adenoma ◽  
Pituitary Adenomas ◽  
Mitochondrial Protein ◽  
Pituitary Tumors ◽  
Pituitary Cells ◽  
Subcellular Compartment ◽  
Adenoma Cell ◽  
Macrophage Colony ◽  
Reduced Rate ◽  
Acth Secreting

Pituitary tumors are mostly benign, being locally invasive in 5–35% of cases. Deregulation of several genes has been suggested as a possible alteration underlying the development and progression of pituitary tumors. We here report the identification of a cDNA, corresponding to Magmas gene (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction), which is highly expressed in two different ACTH-secreting mouse pituitary adenoma cell lines as compared with normal pituitary as well as in two thirds of 64 examined pituitary adenomas as compared with human normal pituitary. Tim 16, the mitochondrial protein encoded by Magmas, was indeed expressed in a mouse ACTH-secreting pituitary adenoma cell line, AtT-20 D16v-F2 cells, in a subcellular compartment likely corresponding to mitochondria. Magmas silencing determined a reduced rate of DNA synthesis, an accumulation in G1 phase, and a concomitant decrease in S phase in At-T20 D16v-F2 cells. Moreover, Magmas-silenced cells displayed basal caspase 3/7 activity and DNA fragmentation levels similar to control cells, which both increased under proapoptotic stimuli. Our data demonstrate that Magmas is overexpressed in mouse and human ACTH-secreting pituitary adenomas. Moreover, our results show that Magmas protects pituitary cells from apoptosis, suggesting its possible involvement in neoplastic transformation.

The effect of d-fenfluramine on anterior pituitary hormone release in the rat: in vivo and in vitro studies

1987 ◽  
Vol 65 (12) ◽  
pp. 2449-2453 ◽  
Author(s):  
O. Serri ◽  
E. Rasio
Keyword(s):  
Growth Hormone ◽  
Male Rats ◽  
Serum Prolactin ◽  
Pituitary Hormone ◽  
Pituitary Cells ◽  
Hormone Release ◽  
Growth Hormone Release ◽  
Serum Growth Hormone

Administration of d-fenfluramine, a serotonin-releasing drug, to male rats induced a dose-dependent increase in both serum prolactin and corticosterone concentrations. Serum growth hormone levels increased, but not significantly, at a dose of 1.25 mg/kg i.p. and decreased significantly at higher doses. When rats were pretreated with the serotonin uptake inhibitor fluoxetine (10 mg/kg i.p.) 30 min prior to injection of d-fenfluramine (5 mg/kg i.p.), the serum prolactin response to d-fenfluramine was partially inhibited, whereas the growth hormone response was not significantly modified. Fluoxetine pretreatment increased the serum corticosterone to the same level as did d-fenfluramine. d-Fenfluramine's effect on prolactin and growth hormone release was further tested in a hypothalamic–pituitary in vitro system. The addition of d-fenfluramine (5–500 ng/mL) for 30 min to rat hypothalami resulted in an enhancement of prolactin and growth hormone-releasing activities. These were expressed as the ability of the media in which the hypothalami had been incubated to stimulate prolactin and growth hormone release by cultured pituitary cells. The data suggest that the effect of d-fenfluramine on prolactin secretion is exerted through the hypothalamus and is probably mediated, at least partially, by a serotoninergic mechanism. The mechanism of d-fenfluramine's effect on corticosterone and growth hormone release needs further evaluation.

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