scholarly journals ALK7 expression in prolactinoma is associated with reduced prolactin and increased proliferation

2018 ◽  
Vol 25 (9) ◽  
pp. 795-806 ◽  
Author(s):  
M Principe ◽  
M Chanal ◽  
V Karam ◽  
A Wierinckx ◽  
I Mikaélian ◽  
...  
Keyword(s):  
Retrospective Analysis ◽  
Signalling Pathways ◽  
Type I ◽  
Human Tumour ◽  
Pituitary Tumours ◽  
Prolactin Cells ◽  
Ki67 Expression ◽  
Unknown Mechanism ◽  
Pituitary Development ◽  
Bmp Signalling

Prolactinoma represents the most frequent hormone-secreting pituitary tumours. These tumours appear in a benign form, but some of them can reach an invasive and aggressive stage through an unknown mechanism. Discovering markers to identify prolactinoma proliferative and invading character is therefore crucial to develop new diagnostic/prognostic strategies. Interestingly, members of the TGFβ-Activin/BMP signalling pathways have emerged as important actors of pituitary development and adult function, but their role in prolactinomas remains to be precisely determined. Here, using a heterotopic allograft model derived from a rat prolactinoma, we report that the Activins orphan type I receptor ALK7 is ectopically expressed in prolactinomas-cells. Through immunohistological approaches, we further confirm that normal prolactin-producing cells lack ALK7-expression. Using a series of human tumour samples, we show that ALK7 expression in prolactinomas cells is evolutionary conserved between rat and human. More interestingly, our results highlight that tumours showing a robust expression of ALK7 present an increased proliferation as address by Ki67 expression and retrospective analysis of clinical data from 38 patients, presenting ALK7 as an appealing marker of prolactinoma aggressiveness. Beside this observation, our work pinpoints that the expression of prolactin is highly heterogeneous in prolactinoma cells. We further confirm the contribution of ALK7 in these observations and the existence of highly immunoreactive prolactin cells lacking ALK7 expression. Taken together, our observations suggest that Activin signalling mediated through ALK7 could therefore contribute to the hormonal heterogeneity and increased proliferation of prolactinomas.

scholarly journals DDX3 directly facilitates IKKα activation and regulates downstream signalling pathways

2018 ◽  
Vol 475 (22) ◽  
pp. 3595-3607 ◽  
Author(s):  
Anthony Fullam ◽  
Lili Gu ◽  
Yvette Höhn ◽  
Martina Schröder
Keyword(s):  
Nuclear Factor Κb ◽  
Innate Immune ◽  
Type I Interferons ◽  
Signalling Pathways ◽  
Type I ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Disease States ◽  
Dead Box ◽  
Iκb Kinase

DDX3 is a DEAD-box RNA helicase that we and others have previously implicated in antiviral immune signalling pathways leading to type I interferon (IFN) induction. We previously demonstrated that it directly interacts with the kinase IKKε (IκB kinase ε), enhances it activation, and then facilitates phosphorylation of the transcription factor IRF3 by IKKε. However, the TLR7/9 (Toll-like receptor 7/9)-mediated pathway, one of the most physiologically relevant IFN induction pathways, proceeds independently of IKKε or the related kinase TBK1 (TANK-binding kinase 1). This pathway induces type I IFN production via the kinases NIK (NF-κB-inducing kinase) and IKKα and is activated when plasmacytoid dendritic cells sense viral nucleic acids. In the present study, we demonstrate that DDX3 also directly interacts with IKKα and enhances its autophosphorylation and -activation. Modulation of DDX3 expression consequently affected NIK/IKKα-mediated IRF7 phosphorylation and induction of type I interferons. In addition, alternative NF-κB (nuclear factor-κB) activation, another pathway regulated by NIK and IKKα, was also down-regulated in DDX3 knockdown cells. This substantially broadens the effects of DDX3 in innate immune signalling to pathways beyond TBK1/IKKε and IFN induction. Dysregulation of these pathways is involved in disease states, and thus, our research might implicate DDX3 as a potential target for their therapeutic manipulation.

An arms race: innate antiviral responses and counteracting viral strategies

2007 ◽  
Vol 35 (6) ◽  
pp. 1512-1514 ◽  
Author(s):  
M. Schröder ◽  
A.G. Bowie
Keyword(s):  
Nuclear Factor Κb ◽  
Signalling Pathways ◽  
Type I ◽  
Nuclear Factor ◽  
Regulatory Factor ◽  
Antiviral Responses ◽  
Type I Ifns ◽  
Activation Of Transcription ◽  
Molecular Patterns ◽  
Pro Inflammatory Cytokines

Viral recognition is mediated by different classes of PRRs (pattern-recognition receptors) among which the TLRs (Toll-like receptors) and the RLHs [RIG (retinoic-acid-inducible)-like helicases] play major roles. The detection of PAMPs (pathogen-associated molecular patterns) by these PRRs leads to the initiation of signalling pathways that ultimately result in the activation of transcription factors such as NF-κB (nuclear factor κB) and IRF-3 [IFN (interferon) regulatory factor-3] and IRF-7 and the induction of pro-inflammatory cytokines and type I IFNs. Viruses have evolved a fine-tuned mechanism to evade detection by the immune system or to interfere with the resulting signalling pathways. Here, we discuss viral evasion proteins that specifically interfere with TLR and/or RLH signalling.

scholarly journals Versatility of USP18 in physiology and pathophysiology

2019 ◽  
Author(s):  
Paulina Dziamałek-Macioszczyk ◽  
Joanna Haraźna ◽  
Tomasz Stompór
Keyword(s):  
Bacterial Infections ◽  
Current Knowledge ◽  
Cell Signalling ◽  
Signalling Pathways ◽  
Type I ◽  
Multifunctional Protein ◽  
Enzymatic Function ◽  
Multiple Processes ◽  
Specific Protease ◽  
Interferon Stimulated Gene 15

Ubiquitin-specific peptidase 18 (USP18) is a multifunctional protein and its roles are still being investigated. This enzyme removes ubiquitin-like molecules from their substrates and the only known interferon-stimulated gene 15 (ISG15) specific protease. Apart from its enzymatic function, it also inhibits interferon type I and III signalling pathways. USP18 is known to regulate multiple processes, such as: cell cycle, cell signalling and response to viral and bacterial infections. Moreover, it contributes to the development of several autoimmune diseases and carcinogenesis, and recently was described as a cardiac remodelling inhibitor. This review summarizes the current knowledge on USP18 functions, highlighting its contribution to the development of heart failure, given the fact that this disease’s etiology is now considered to be inflammatory in nature.

scholarly journals Insight into Gene Polymorphisms Involved in Toll-Like Receptor/Interferon Signalling Pathways for Systemic Lupus Erythematosus in South East Asia

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Hwa Chia Chai ◽  
Kek Heng Chua ◽  
Soo Kun Lim ◽  
Maude Elvira Phipps
Keyword(s):  
Lupus Erythematosus ◽  
Meta Analysis ◽  
Signalling Pathways ◽  
Type I ◽  
Nucleotide Polymorphisms ◽  
Toll Like Receptor ◽  
Single Nucleotide ◽  
Asian Populations ◽  
Interferon Signalling

Polymorphisms in genes involved in toll-like receptor/interferon signalling pathways have been reported previously to be associated with SLE in many populations. This study aimed to investigate the role of seven single nucleotide polymorphisms withinTNFAIP3,STAT4,andIRF5, which are involved in upstream and downstream pathways of type I interferon production, in SLE in the South East Asian populations. Genotyping of 360 Malaysian SLE patients and 430 normal healthy individuals revealed that minor alleles ofSTAT4rs7574865 and rs10168266 were associated with elevated risk of SLE in the Chinese and Malay patients, respectively (P=0.028, odds ratio(OR)=1.42;P=0.035,OR=1.80, respectively). Polymorphisms inTNFAIP3andIRF5did not show significant associations with SLE in any of the ethnicities. Combined analysis of the Malays, Chinese, and Indians for each SNP indicated thatSTAT4rs10168266 was significantly associated with the Malaysian SLE as a whole (P=0.014;OR=1.435). The meta-analysis ofSTAT4rs10168266, which combined the data of other studies and this study, further confirmed its importance as the risk factor for SLE by having pooled OR of 1.559 andPvalue of <0.001.

Differential control of type-I iodothyronine deiodinase expression by the activation of the cyclic AMP and phosphoinositol signalling pathways in cultured human thyrocytes

1995 ◽  
Vol 14 (2) ◽  
pp. 171-177 ◽  
Author(s):  
S G Beech ◽  
S W Walker ◽  
J R Arthur ◽  
D Lee ◽  
G J Beckett
Keyword(s):  
Cyclic Amp ◽  
Calcium Ionophore ◽  
Calcium Ionophore A23187 ◽  
Signalling Pathways ◽  
Cell Labelling ◽  
Ionophore A23187 ◽  
Type I ◽  
Iodothyronine Deiodinase ◽  
Differential Control ◽  
Stimulation Of

ABSTRACT The effects of TSH and the activation of the cyclic AMP (cAMP) and Ca2+-phosphatidylinositol (Ca2+-PI) cascades on the activity and expression of the selenoenzyme thyroidal type-I iodothyronine deiodinase (ID-I) have been studied using human thyrocytes grown in primary culture. Stimulation of ID-I activity and expression was obtained with TSH and an analogue of cAMP, 8-bromo-cAMP. In the presence or absence of TSH, the addition of the phorbol ester, phorbol 12-myristate 13-acetate (PMA) together with the calcium ionophore A23187, caused a decrease in ID-I activity; a decrease in ID-I expression was also observed as assessed by cell labelling with [75 Se]selenite. PMA alone had no effect on ID-I activity in the presence or absence of TSH. A23187 alone produced a small but significant reduction in ID-I activity, but only in TSH-stimulated cells. These data provide evidence that the expression of thyroidal ID-I is negatively regulated by the Ca2+-PI cascade, and positively regulated by the cAMP cascade.

scholarly journals TRIM24 facilitates antiviral immunity through mediating K63-linked TRAF3 ubiquitination

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Qingchen Zhu ◽  
Tao Yu ◽  
Shucheng Gan ◽  
Yan Wang ◽  
Yifei Pei ◽  
...  
Keyword(s):  
Virus Infection ◽  
Vesicular Stomatitis Virus ◽  
Rna Virus ◽  
Antiviral Immunity ◽  
Type I ◽  
Antiviral Signaling ◽  
Unknown Mechanism ◽  
Positive Regulator ◽  
Transcriptional Suppression ◽  
Vesicular Stomatitis

Ubiquitination is an essential mechanism in the control of antiviral immunity upon virus infection. Here, we identify a series of ubiquitination-modulating enzymes that are modulated by vesicular stomatitis virus (VSV). Notably, TRIM24 is down-regulated through direct transcriptional suppression induced by VSV-activated IRF3. Reducing or ablating TRIM24 compromises type I IFN (IFN-I) induction upon RNA virus infection and thus renders mice more sensitive to VSV infection. Mechanistically, VSV infection induces abundant TRIM24 translocation to mitochondria, where TRIM24 binds with TRAF3 and directly mediates K63-linked TRAF3 ubiquitination at K429/K436. This modification of TRAF3 enables its association with MAVS and TBK1, which consequently activates downstream antiviral signaling. Together, these findings establish TRIM24 as a critical positive regulator in controlling the activation of antiviral signaling and describe a previously unknown mechanism of TRIM24 function.

scholarly journals Blockage of bone morphogenetic protein signalling counteracts hypertrophy in a human osteoarthritic micro-cartilage model

2020 ◽  
Vol 133 (23) ◽  
pp. jcs249094 ◽  
Author(s):  
Shikha Chawla ◽  
Majoska H. M. Berkelaar ◽  
Boris Dasen ◽  
Christine Halleux ◽  
Sabine Guth-Gundel ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Selective Inhibition ◽  
Type I ◽  
Mesenchymal Progenitors ◽  
Morphogenetic Protein ◽  
Cartilage Extracellular Matrix ◽  
Embryonic Cartilage ◽  
Oa Chondrocytes ◽  
Bmp Signalling

ABSTRACTBone morphogenetic protein (BMP) signalling plays a significant role during embryonic cartilage development and has been associated with osteoarthritis (OA) pathogenesis, being in both cases involved in triggering hypertrophy. Inspired by recent findings that BMP inhibition counteracts hypertrophic differentiation of human mesenchymal progenitors, we hypothesized that selective inhibition of BMP signalling would mitigate hypertrophic features in OA cartilage. First, a 3D in vitro OA micro-cartilage model was established using minimally expanded OA chondrocytes that was reproducibly able to capture OA-like hypertrophic features. BMP signalling was then restricted by means of two BMP receptor type I inhibitors, resulting in reduction of OA hypertrophic traits while maintaining synthesis of cartilage extracellular matrix. Our findings open potential pharmacological strategies for counteracting cartilage hypertrophy in OA and support the broader perspective that key signalling pathways known from developmental processes can guide the understanding, and possibly the mitigation, of adult pathological features.

Role of the ovary in the sexual differentiation of prolactin and growth hormone cells in the mouse adenohypophysis: a stereological morphometric study by electron microscopy

1982 ◽  
Vol 93 (1) ◽  
pp. 117-121 ◽  
Author(s):  
Fumihiko Sasaki ◽  
Masao Sano
Keyword(s):  
Growth Hormone ◽  
Adult Female ◽  
Morphometric Study ◽  
Vaginal Opening ◽  
Prolactin Cells ◽  
Pituitary Development ◽  
Plateau Level ◽  
Stimulation Of ◽  
Male Pattern

The number of prolactin and growth hormone cells was estimated in the mouse anterior pituitary gland. During postnatal development in females, the number of prolactin cells showed a rectilinear increase from about 0·3 × 104 at 20 days of age to about 21 × 104 in adult female mice, while growth hormone cells gradually increased from about 7 × 104 on day 20 to about 20 × 104 on days 60–70, with a plateau level of about 14 × 104 cells around puberty. Prolactin cells were more abundant in adult female (about 21 × 104) than in male (about 5 × 104) mice, while there were fewer growth hormone cells in adult females (about 20 × 104) than in males (about 25 × 104). Ovariectomy before puberty induced the male pattern of pituitary development by inhibition of the increase in the number of prolactin cells and stimulation of that of growth hormone cells. In animals ovariectomized just before puberty (30–35 days of age) or 5 days after vaginal opening (40–45 days of age) the number of prolactin cells showed no further increase after the day of operation. On the other hand, when animals were ovariectomized at 10 days of age, the number of prolactin cells increased to the level found in 30-day-old normal control females. This implies that the increase in prolactin cells between 10 and 30 days of age is not dependent on the ovary, although after puberty the increase does depend on the presence of the ovary.

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