Cross-talk between steroid-receptor-mediated and cell-membrane-receptor-mediated signalling pathways results in the in vivo modulation of c-Met and ornithine decarboxylase gene expression in mouse kidney

2001 ◽  
Vol 353 (2) ◽  
pp. 317-323 ◽  
Author(s):  
Magdalena DUDKOWSKA ◽  
Agnieszka STACHURSKA ◽  
Wanda CHMURZYŃSKA ◽  
Barbara GRZELAKOWSKA-SZTABERT ◽  
Małgorzata MANTEUFFEL-CYMBOROWSKA
Keyword(s):  
Gene Expression ◽  
Ornithine Decarboxylase ◽  
Cross Talk ◽  
Mrna Level ◽  
Signalling Pathways ◽  
Renal Tubules ◽  
The Cross ◽  
Transient Elevation ◽  
Hepatocyte Growth

The cross-talk in vivo between two signalling pathways activated by testosterone via intracellular androgen receptor, and induced by damage to renal tubules evoked by anti-folate [N10-propargyl-5,8-dideazafolic acid (CB 3717)] or folate is reported. We show that CB 3717/folate induces the expression of the hepatocyte growth factor (HGF)/c-Met signalling system in injured kidneys in which a significant, but transient, elevation of the HGF mRNA level occurs. It is followed by a severalfold increase in the c-Met transmembrane receptor message that persists for up to 24h. The c-Met expression is also positively controlled by testosterone, which induces a significant increase in its mRNA level that is abolished by an anti-androgen, casodex. However, when testosterone and anti-folate/folate are administered sequentially, a substantial (3.5Ő4.0-fold) decrease in the increase of c-Met expression caused by CB 3717/folate alone occurs. Similarly, testosterone-induced ornithine decarboxylase (ODC) mRNA level and activity are decreased 2.8Ő7.7-fold when the androgen is applied together with CB 3717. Antagonism between these pathways is also visible under physiological conditions in the kidneys of male mice in which, owing to elevated endogenous testosterone levels, neither the ODC activity nor the mRNA level is induced by anti-folate/folate, whereas the c-Met message response to these drugs is significantly decreased. Our results document a substantial negative regulation of c-Met and ODC gene expression as a result of the cross-talk between testosterone-activated and HGF-activated pathways and suggest a sex-differentiated response to injury of mouse kidneys.

Lithium regulates PKC-mediated intracellular cross-talk and gene expression in the CNS in vivo

2000 ◽  
Vol 2 (3p2) ◽  
pp. 217-236 ◽  
Author(s):  
Guang Chen ◽  
Monica I Masana ◽  
Husseini K Manji
Keyword(s):  
Gene Expression ◽  
Cross Talk

Differential effects of phorbol esters on c-fos and c-myc and ornithine decarboxylase gene expression in mouse skin in vivo

1988 ◽  
Vol 9 (5) ◽  
pp. 831-835 ◽  
Author(s):  
S. Rose-John ◽  
G. Fürstenberger ◽  
P. Krieg ◽  
E. Besemfelder ◽  
G. Rincke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ornithine Decarboxylase ◽  
Phorbol Esters ◽  
Mouse Skin ◽  
Differential Effects

scholarly journals Revealing the bovine embryo transcript profiles during early in vivo embryonic development

Reproduction ◽  
2009 ◽  
Vol 138 (1) ◽  
pp. 95-105 ◽  
Author(s):  
Maud Vallée ◽  
Isabelle Dufort ◽  
Stéphanie Desrosiers ◽  
Aurélie Labbe ◽  
Catherine Gravel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Embryonic Development ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Current Knowledge ◽  
Mrna Level ◽  
Early Embryonic Development ◽  
Bovine Embryo ◽  
Rna Content

Gene expression profiling is proving to be a powerful approach for the identification of molecular mechanisms underlying complex cellular functions such as the dynamic early embryonic development. The objective of this study was to perform a transcript abundance profiling analysis of bovine early embryonic development in vivo using a bovine developmental array. The molecular description of the first week of life at the mRNA level is particularly challenging when considering the important fluctuations in RNA content that occur between developmental stages. Accounting for the different intrinsic RNA content between developmental stages was achieved by restricting the reaction time during the global amplification steps and by using spiked controls and reference samples. Analysis based on intensity values revealed that most of the transcripts on the array were present at some point during in vivo bovine early embryonic development, while the varying number of genes detected in each developmental stage confirmed the dynamic profile of gene expression occurring during embryonic development. Pair-wise comparison of gene expression showed a marked difference between oocytes and blastocysts profiles, and principal component analysis revealed that the majority of the transcripts could be regrouped into three main clusters representing distinct RNA abundance profiles. Overall, these data provide a detailed temporal profile of the abundance of mRNAs revealing the richness of signaling processes in early mammalian development. Results presented here provide better knowledge of bovine in vivo embryonic development and contribute to the progression of our current knowledge regarding the first week of life in mammals.

scholarly journals Ultraviolet B radiation induction of ornithine decarboxylase gene expression in mouse epidermis

1990 ◽  
Vol 270 (3) ◽  
pp. 565-568 ◽  
Author(s):  
C F Rosen ◽  
D Gajic ◽  
Q Jia ◽  
D J Drucker
Keyword(s):  
Gene Expression ◽  
Ornithine Decarboxylase ◽  
Hairless Mouse ◽  
Ultraviolet B ◽  
Dependent Manner ◽  
Mouse Epidermis ◽  
Cellular Effects ◽  
Mrna Transcripts ◽  
Maximal Induction

The cellular effects of u.v. radiation have been studied by using a hairless-mouse model in vivo. U.v. B radiation (u.v.B) induced the activity of the enzyme ornithine decarboxylase (ODC) in mouse epidermis. Maximal induction was noted after radiation with 90 mJ/cm2, and increased ODC activity was first detected 2 h after u.v.B exposure. U.v.B. also induced the expression of the ODC gene in a time- and dose-dependent manner, but did not induce the levels of actin mRNA transcripts. Cycloheximide treatment did not alter basal levels of ODC mRNA transcripts and had no effect on the u.v.B induction of ODC-gene expression. The results of these experiments demonstrate that u.v.B radiation induces both the expression of the ODC gene and the activity of the enzyme, and provides a useful ‘in vivo’ paradigm for the analysis of the molecular effects of u.v.B radiation.

scholarly journals Androgen receptor and c-Myc transcription factors as putative partners in the in vivo cross-talk between androgen receptor-mediated and c-Met-mediated signalling pathways.

2007 ◽  
Vol 54 (2) ◽  
pp. 253-259 ◽  
Author(s):  
Magdalena Dudkowska ◽  
Tomasz Jaworski ◽  
Barbara Grzelakowska-Sztabert ◽  
Małgorzata Manteuffel-Cymborowska
Keyword(s):  
Transcription Factors ◽  
Androgen Receptor ◽  
Cross Talk ◽  
Protein Level ◽  
Target Genes ◽  
Pronounced Increase ◽  
Mrna Content ◽  
Functional Consequences ◽  
Hepatocyte Growth

Cross-talk between two signal transduction pathways leads to a negative regulation of androgen-induced ornithine decarboxylase (ODC) gene expression in the mouse kidney. One pathway is triggered by testosterone via the intracellular androgen receptor, AR, and the other is induced by antifolate CB 3717 or folate via hepatocyte growth factor and its cell membrane receptor c-Met. Here we report the studies of the expression of AR and c-Myc transcription factors involved in ODC transactivation. Administration of CB 3717 or folate decreased the expression of AR. In contrast, testosterone did not modify AR mRNA content but augmented the AR protein. Furthermore, we demonstrate that administration of folate, but not testosterone, increases c-Myc transcript and protein level. We also document that activation of both examined pathways does not decrease the testosterone-induced AR protein level, but markedly increases c-Myc protein which is nearly 2-fold up-regulated compared to its level evoked solely by testosterone. We suspect that this pronounced increase of c-Myc protein might have functional consequences mirrored by down-regulated expression of AR target genes, among them ODC.

Fc Receptor Targeting Reduces Bone Disease in a Pre-Clinical Model of Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3011-3011
Author(s):  
Mark T Williams ◽  
Katya Thümmler ◽  
Susan Kitson ◽  
Richard Soutar ◽  
Carl S Goodyear
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Signalling Pathways ◽  
Micro Ct ◽  
Cell Injection ◽  
Clinical Model ◽  
Rank Gene

Abstract Background: Multiple Myeloma (MM) is currently incurable, with a median survival of 5-7 years post diagnosis. MM-associated bone disease (MM-OBD), represents a major cause of morbidity and mortality in MM patients. Despite current therapies for MM-OBD exhibiting significant potential (e.g. Zoledronate), their clinical use has been restricted due to severe treatment associated toxicities. Safe novel therapies for MM-OBD are therefore crucially required. Molecular crosstalk between receptor activator of nuclear factor Kappa B ligand (RANKL), present on and secreted by MM plasma cells, and its corresponding receptor (RANK) on osteoclast precursors (OCPs), represents a key mechanism driving osteoclastogenesis and subsequent bone pathology in MM. Our previous studies have demonstrated that Fc receptor (FcR)-mediated signals can inhibit RANKL induced osteoclastogenesis in vitro1. In addition, findings from preliminary studies show that FcR-mediated signalling in pre-osteoclasts can reduce MM plasma cell driven osteoclastogenesis in vitro. Further interrogation of the underlying molecular mechanisms show that FcR-mediated signals profoundly reduce RANK transcript, and subsequent protein expression, in pre-osteoclasts. However, the effects of FcR engagement on MM-OBD in vivo, and the FcR elicited signalling pathways responsible for inhibition of RANK expression have still to be elucidated. Aims: This study aimed to determine the in vivo potential of FcR engagement to treat bone disease in a pre-clinical model of MM. Additionally, the mechanisms underlyingFcR-mediated down-regulation of RANK expression in OCPs were interrogated. Methods: The well-characterised 5TGM1 murine model of MM, together with micro-computed topography (micro-CT), were used to evaluate the effect of FcR engagement on MM-OBD. FcR stimulation was achieved by I.P. injecting mice (every other day, following 5TGM1 I.V. cell injection), with 100 μg/ml of Protein A derived from Staphylococcus aureus (SpA). SpA has been shown to form small immune complexes (SICs) through its affinity for endogenous IgG, which in turn binds to FcγR1 receptors on monocytes and pre-OCs1. Additionally, the potential involvement of FcR signalling pathways in the down-regulation of RANK in healthy and MM-derived human OCPs was determined via immunoblotting and the use of signalling pathway inhibitors. Results: Twenty six days post-myeloma cell injection, micro-CT analysis of femurs revealed that mice receiving PBS (vehicle control, n=5) exhibited a significant decrease in bone morphmetric parameters consistent with bone erosion compared to non-myeloma bearing mice (n=3); trabecullar bone volume [BV/TV] = 2.673 vs. 3.449, p=0.034; trabecullar number [Tb.N] = 0.0035 vs. 0.0042, p=0.0041; trabecullar pattern factor [Tb.Pf] = 0.2329 vs. 0.2033, p=0.0393. Importantly, myeloma bearing mice (n=5) receiving SpA, were protected from MM-OBD. In human OCPs (sourced from healthy individuals and MM patients), FcR engagement substantially activated SyK, MEK-ERK1/2, and PI3K signaling cascades. However, inhibition of these pathways failed to restore RANK transcript levels. Discussion: These findings demonstrate novel mechanisms of RANK gene expression regulation in healthy and MM OCPs, with Fc receptors representing a potential therapeutic strategy for MM-OBD. Further studies will aim to elucidate the molecular mechanisms responsible for FcR-mediated regulation of RANK gene expression. 1. MacLellan, L. M. et al. Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis Rheum.63, 3897-3907 (2011). Disclosures No relevant conflicts of interest to declare.

In vivo antioxidant gene expression in human airway epithelium of normal individuals exposed to 100% O2

1993 ◽  
Vol 75 (3) ◽  
pp. 1256-1262 ◽  
Author(s):  
S. C. Erzurum ◽  
C. Danel ◽  
A. Gillissen ◽  
C. S. Chu ◽  
B. C. Trapnell ◽  
...  
Keyword(s):  
Gene Expression ◽  
Airway Epithelium ◽  
Oxidant Stress ◽  
Mrna Level ◽  
Bronchial Epithelium ◽  
Antioxidant Gene ◽  
Human Airway ◽  
Human Airway Epithelium ◽  
Antioxidant Gene Expression

Human bronchial epithelium is exquisitely sensitive to high O2 levels, with tracheobronchitis usually developing after 12 h of exposure to 100% O2. To evaluate whether this vulnerability results from inability of the bronchial epithelium to provide adequate antioxidant protection, we quantified antioxidant gene expression in bronchial epithelium of normal volunteers at baseline and after exposure to 100% O2 in vivo. After 14.8 +/- 0.2 h of 100% O2, 24 of 33 individuals had evidence of tracheobronchitis. Baseline gene expression of CuZn superoxide dismutase (SOD), MnSOD, and catalase in bronchial epithelium was very low (CuZnSOD 4.1 +/- 0.8 transcripts/cell, MnSOD 5.1 +/- 0.9, catalase 1.3 +/- 0.2), with control gamma-actin expression relatively abundant (50 +/- 6 transcripts/cell). Importantly, despite 100% O2 exposure sufficient to cause tracheobronchitis in most individuals, antioxidant mRNA transcripts/cell in bronchial epithelium did not increase (P > 0.5). Catalase activity in bronchial epithelium did not change after exposure to hyperoxia (P > 0.05). Total SOD activity increased mildly (P < 0.01) but not sufficiently to protect the epithelium. Together, the very low levels of expression of intracellular antioxidant enzymes and the inability to upregulate expression at the mRNA level with oxidant stress likely have a role in human airway epithelium susceptibility to hyperoxia.

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