Nadia Cherradi

INSERM - Commissariat à l'Energie Atomique - Université Grenoble Alpes · Institut de Recherche Interdisciplinaire de Grenoble - CEA

Disclosure: I. Hani: None. T. Vu: None. R. Brillet: None. J. Perrot: None. J. Bouligand: None. J. Guegan: None. N. Cherradi: None. P. Kamenicky: None. M. Lombes: None. L. Martinerie: None. S. Viengchareun: None. In tight epithelia, aldosterone controls sodium and water homeostasis by binding to the Mineralocorticoid Receptor (MR), a steroid nuclear...

Adrenocortical carcinoma (ACC) is a rare malignancy with dismal prognosis. Deregulated microRNA (miRNA) expression has been implicated in ACC aggressiveness. Nevertheless, the mechanisms underlying such deregulations remain unknown. Aberrant Wnt/β-Catenin signaling has been reported in about 40% of ACC and is associated with poor outcome. Here, we...

Introduction Des essais cliniques récents suggèrent que les microARN sont des cibles thérapeutiques prometteuses en oncologie. Nous avons montré que la surexpression de miR-139-5p et miR-483-5p est associée à l’agressivité du carcinome corticosurrénalien (CCS). L’objectif de cette étude est d’évaluer le potentiel thérapeutique d’inhibiteurs de miR-...

Simple Summary Cancer is a complex disease associated with deregulation of numerous genes. In addition, redundant cellular pathways limit efficiency of monotarget drugs in cancer therapy. MicroRNAs are a class of gene expression regulators, which often function by targeting multiple genes. This feature makes them a double-edged sword (a) as attract...

Background In this exploratory study, the impact of local irradiation on systemic changes in stress and immune parameters was investigated in eight patients treated with intensity-modulated radiation therapy (IMRT) or stereotactic ablative body radiotherapy (SABR) for prostate adenocarcinoma to gain deeper insights into how radiotherapy (RT) modula...

Introduction Certains microARN (miRs) du locus soumis à empreinte parentale 14q32 sont surexprimés dans les carcinomes corticosurrénaliens (CCS) agressifs (récidivants/métastatiques) comparés aux CCS indolents et aux adénomes [1]. Par ailleurs, des mutations activatrices de la voie Wnt/β-caténine (β-cat) sont retrouvées dans 39 % des CCS [2]. Obje...

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the regulation of major pathways in eukaryotic cells through their binding to and repression of multiple mRNAs. With high-throughput methodologies, various outcomes can be measured that produce long lists of miRNAs that are often difficult to interpret. A common question is: after di...

We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor progn...

MicroRNAs (miRNAs) are small non-coding RNAs that are involved in the regulation of major pathways in eukaryotic cells through repression of their target genes at the post-transcriptional level. While high-throughput approaches are broadly used to decipher the biological relevance of miRNAs, extraction of significant information from large miRNA da...

Anti-silencing function 1 (ASF1) is a conserved H3-H4 histone chaperone involved in histone dynamics during replication, transcription, and DNA repair. Overexpressed in proliferating tissues including many tumors, ASF1 has emerged as a promising therapeutic target. Here, we combine structural, computational, and biochemical approaches to design pep...

Altered expression of regulatory RNA-binding proteins (RBPs) in cancer leads to abnormal expression of mRNAs encoding many factors involved in cancer hallmarks. While conventional anticancer therapies usually target one pathway at a time, targeting key RBP would affect multiple genes and thus overcome drug resistance. Among the Tristetraprolin fami...

Introduction Le carcinome corticosurrénalien (CCS) a besoin de meilleurs marqueurs diagnostiques et pronostiques. Nous avons récemment démontré que les microARN miR-483-5p et miR-139-5p sont sur-exprimés dans les CCS où ils ciblent les gènes N-myc Downstream-Regulated Gene (NDRG) 2 et 4 (Agosta et al., International Journal of Cancer, 2018). Objec...

Adrenocortical carcinoma (ACC) is a tumor with poor prognosis in which overexpression of a panel of microRNAs has been associated with malignancy but a very limited number of investigations on their role in ACC pathogenesis have been conducted. We examined the involvement of miR-483-5p and miR-139-5p in adrenocortical cancer aggressiveness. Using b...

Mineralocorticoid receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron. Herein, we decipher mechanisms by which hypotonicity increases MR expression in renal principal cells. We identify HuR (human antigen R), an mRNA-stabilizing protein, as an important posttranscriptional regulator of MR expression. Hypotonicity...

Aldosterone and the Mineralocorticoid Receptor (MR) control hydroelectrolytic homeostasis and alterations of mineralocorticoid signaling pathway are involved in the pathogenesis of numerous human diseases, justifying the need to decipher molecular events controlling MR expression level. Here, we show in renal cells that the RNA-Binding Protein, Hum...

The regulation of mRNA stability has emerged as a critical control step in dynamic gene expression. This process occurs in response to modifications of the cellular environment, including hormonal variations, and regulates the expression of subsets of proteins whose levels need to be rapidly adjusted. Modulation of messenger RNA stability is usuall...

The regulation of mRNA stability has emerged as a critical control step in dynamic gene expression. This process occurs in response to modifications of the cellular environment, including hormonal variations, and regulates the expression of subsets of proteins whose levels need to be rapidly adjusted. Modulation of messenger RNA stability is usuall...

TIS11b/BRF1 belongs to the Tristetraprolin (TTP) family of zinc-finger proteins which bind to mRNAs containing AU-rich elements (ARE) in their 3'-untranslated region and target them for degradation. Regulation of TTP family function through phosphorylation by p38 MAPK and PKB/Akt signalling pathways has been extensively studied. In contrast, the ro...

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis and limited therapeutic options. Over the last decade, pan-genomic analyses of genetic and epigenetic alterations and genome-wide expression profile studies allowed major advances in the understanding of the molecular genetics of ACC. Besides the well-known dysfunctional molecu...

Angiogenesis is a finely tuned process that is tightly regulated in time and space by environmental factors (oxygen levels, extracellular matrix, diffusible growth factors, and cytokines). Expression of angiogenesis effectors and regulators is coordinately regulated at both transcriptional and posttranscriptional levels. Accumulating evidence sugge...

The mineralocorticoid receptor (MR) mediates the Na(+)-retaining action of aldosterone. MR is highly expressed in the distal nephron, which is submitted to intense variations in extracellular fluid tonicity generated by the corticopapillary gradient. We previously showed that post-transcriptional events control renal MR abundance. Here, we report t...

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Local and distant recurrences occur in a subset of tumors classified as 'aggressive' ACC (aACC), as opposed to 'non-aggressive' ACC (naACC). In this study, we investigated whether tissue and serum microRNAs (miRNAs) are predictive of ACC prognosis. Tissue miRNA expression profiles...

Members of the tristetraprolin (TTP/TIS11) family are important RNA-binding proteins initially characterized as mediators of mRNA degradation. They act via their interaction with AU-rich elements present in the 3'UTR of regulated transcripts. However, it is progressively appearing that the different steps of mRNA processing and fate including trans...

MicroRNAs (miRNAs) are short non-coding RNAs that are involved in the epigenetic regulation of cellular processes. Different malignancies are often associated with the deregulation of specific sets of miRNAs. The prognosis of adrenocortical cancers (ACCs) is very poor as compared to adrenocortical adenomas (ACAs), and even within ACCs there are cas...

Tis11b/BRF1 belongs to the tristetraprolin family, the members of which are involved in AU-rich-dependent regulation of mRNA stability/degradation. Mouse inactivation of the Tis11b gene has revealed disorganization of the vascular network and up-regulation of the proangiogenic factor VEGF. However, the VEGF deregulation alone cannot explain the phe...

Endothelial cells (ECs) are the primary sensors of variations in blood oxygen concentrations. They use the hypoxia-sensitive stabilization of the hypoxia-inducible factor-1α (HIF-1α) transcription factor to engage specific transcriptional programs in response to oxygen changes. The regulation of HIF-1α expression is well documented at the protein l...

The steroidogenic acute regulatory (StAR) protein is generated in rodents from 1.6 kb and 3.5 kb mRNA formed by alternative polyadenylation. The zinc finger protein, TIS11B (also Znf36L1), is elevated by cAMP in adrenal cells in parallel with StAR mRNA. TIS11b selectively destabilizes the 3.5 kb mRNA through AU-rich sequences at the end of the 3'UT...

Angiogenesis inhibitors have shown clinical benefits in patients with advanced cancer, but further therapeutic improvement is needed. We have previously shown that the zinc finger protein 36, C3H type-like 1 (ZFP36L1) enhances vascular endothelial growth factor (VEGF) mRNA decay through its interaction with AU-rich elements within VEGF 3'-untransla...

Stimulation of cortisol secretion through abnormally expressed G protein-coupled receptors (GPCRs) is a frequent feature of ACTH-independent macronodular adrenal hyperplasia (AIMAH). This has opened a pharmacological strategy that targets GPCRs for the treatment of Cushing's syndrome in AIMAH. However, only few drugs are available for the presently...

Dynamic interactions between components of the outer (OM) and inner (IM) membranes control a number of critical mitochondrial functions such as channeling of metabolites and coordinated fission and fusion. We identify here the mitochondrial AAA+ ATPase protein ATAD3A specific to multicellular eukaryotes as a participant in these interactions. The N...

Aldosterone effects are mediated by the mineralocorticoid receptor (MR), a transcription factor highly expressed in the distal nephron. Given that MR expression level constitutes a key element controlling hormone responsiveness, there is much interest in elucidating the molecular mechanisms governing MR expression. To investigate whether hyper-or h...

Aldosterone effects are mediated by the mineralocorticoid receptor (MR), a transcription factor highly expressed in the distal nephron. Given that MR expression level constitutes a key element controlling hormone responsiveness, there is much interest in elucidating the molecular mechanisms governing MR expression. To investigate whether hyper- or...

Star is expressed in steroidogenic cells as 3.5- and 1.6-kb transcripts that differ only in their 3'-untranslated regions (3'-UTR). In mouse MA10 testis and Y-1 adrenal lines, Br-cAMP preferentially stimulates 3.5-kb mRNA. ACTH is similarly selective in primary bovine adrenocortical cells. The 3.5-kb form harbors AU-rich elements (AURE) in the exte...

Cushing's syndrome due to ACTH-independent macronodular adrenal hyperplasia (AIMAH) can be associated with abnormal responses of aberrantly expressed adrenocortical receptors. This study aimed to characterize in vitro the pathophysiology of hypercortisolism in a beta-blocker-sensitive Cushing's syndrome due to AIMAH. Cortisol secretion profile unde...

Expression of vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen and a potent angiogenic factor, is up-regulated by a variety of factors including hypoxia, growth factors, and hormones. In the adrenal cortex, regulation of VEGF expression by the pituitary hormone ACTH ensures the maintenance of the organ vasculature. We...

The aim of this study was to identify predictor sets of genes whose over- or underexpression in human sporadic adrenocortical tumors would help to identify malignant vs. benign tumors and to predict postsurgical metastatic recurrence. For this, we analyzed the expression of 230 candidate genes using cDNA microarrays in a series of 57 well-character...

Vascular endothelial growth factor (VEGF) is an angiogenic cytokine, which plays a major role in tumor angiogenesis. VEGF mRNA expression is controlled by hypoxia, growth factors and hormones through both transcriptional and post-transcriptional mechanisms. VEGF mRNA has a short half-life and its abundance is regulated by the binding of stabilizing...

In adrenal glomerulosa cells, the stimulation of aldosterone biosynthesis by angiotensin II (Ang II) occurs via activation of the Ca2+ messenger system, increased expression of the steroidogenic acute regulatory protein, and enhanced transfer of cholesterol to the inner mitochondrial membrane. We examined here whether Ang II affects the activity of...

Angiotensin II is one of the main physiological regulators of aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex. The hormone stimulates intracellular cholesterol mobilization to the mitochondrion for steroid biosynthesis. Here we have examined whether angiotensin II also modulates exogenous lipoprotein cholesterol ester supply...

The adipocyte-derived hormone leptin is a central modulator of food intake, metabolism and neuroendocrine functions. It is also involved in a physiological loop linking the activity of the hypothalamo-pituitary-adrenal axis and adipose tissue. At the adrenal level, leptin has been shown to antagonize the effects of ACTH on glucocorticoid biosynthes...

The adipocyte-derived hormone leptin is a central modulator of food intake, metabolism and neuroendocrine functions. It is also involved in a physiological loop linking the activity of the hypothalamo-pituitary-adrenal axis and adipose tissue. At the adrenal level, leptin has been shown to antagonize the effects of ACTH on glucocorticoid biosynthes...

The zona glomerulosa cell of the adrenal cortex produces mineralocorticoids in response to physiological stimuli (angiotensin II and extracellular K+) activating the Ca2+ messenger system. The mechanisms underlying the generation of the Ca2+ signal have been analyzed extensively and recent developments have contributed to bridging the gap between i...

In adrenal zona glomerulosa cells, the calcium messenger system is the major signaling mechanism activated by physiological stimulators of aldosterone production. We present here evidence for a dual site of action of the calcium signal: 1) Calcium influx into the mitochondrion is a prerequisite to the activation of steroidogenesis. This calcium ent...

Atrial natriuretic peptide (ANP) is a potent inhibitor of mineralocorticoid synthesis induced in adrenal glomerulosa cells by physiological agonists activating the calcium messenger system, such as angiotensin II (Ang II) and potassium ion (K+). While the role of calcium in mediating Ang II- and K+-induced aldosterone production is clearly establis...

Transforming growth factor-betas (TGF-betas) constitute a family of dimeric proteins that affect growth and differentiation of many cell types. TGF-beta1 has also been proposed to be an autocrine regulator of adrenocortical steroidogenesis, acting mainly by decreasing the expression of cytochrome P450c17. Here, we demonstrate that TGF-beta1 has a s...

In adrenal glomerulosa cells, angiotensin II (Ang II) and potassium stimulate aldosterone synthesis through activation of the calcium messenger system. The rate-limiting step in steroidogenesis is the transfer of cholesterol to the inner mitochondrial membrane. This transfer is believed to depend upon the presence of the steroidogenic acute regulat...

The role of free calcium as a crucial intracellular messenger in the stimulation of aldosterone biosynthesis by various agonists is well established. Using electropermeabilized or Ca(2+)-clamped adrenal zona glomerulosa (ZG) cells, we have previously shown that Ca2+ entry into the mitochondrial matrix is required for the activation of steroidogenes...

In adrenal glomerulosa cells, angiotensin II (Ang II) stimulates aldosterone synthesis through rises of cytosolic calcium ([Ca2+]c). The rate-limiting step in this process is the transfer of cholesterol to the inner mitochondrial membrane, where it is converted to pregnenolone by the P450 side chain cleavage enzyme. The aim of the present study was...

We have previously reported the co-localization [Cherradi et al., Endocrinology 134 (1994) 1358-1364] of 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD) and cytochrome P450scc (cyt. P450scc) in the inner membrane and in the intermembrane contact sites of adrenocortical mitochondria. This observation raises the question of a possible func...

In the Y1 mouse adrenal tumor cell line, the 3 beta-hydroxysteroid dehydrogenase isomerase enzyme (3 beta-HSD) which catalyzes the transformation of 3 beta-hydroxy-5-ene steroids to 3-keto-4-ene steroids is active. The effect of type beta 1 transforming growth factor (TGF beta 1), a potent modulator of adrenocortical differentiated functions, on th...

In the Y1 mouse adrenal tumor cell line, the 3β-hydroxysteroid dehydrogenase isomerase enzyme (3β-HSD) which catalyzes the transformation of 3β-hydroxy-5-ene steroids to 3-keto-4-ene steroids is active. The effect of type β1 transforming growth factor (TGFβ1), a potent modulator of adrenocortical differentiated functions, on the 3β-HSD enzyme was s...

The enzymatic activity of 3 beta-hydroxysteroid dehydrogenase (3 beta HSD/I) constitutes an essential step in the biosynthesis of active steroid hormones such as progesterone, mineralo- and gluco-corticoids, estrogens, and androgens. Its subcellular localization in steroidogenic tissues is usually considered to be mainly microsomal; however, 3 beta...

The enzymatic activity of 3 beta-hydroxysteroid dehydrogenase (3 beta HSD/I) constitutes an essential step in the biosynthesis of active steroid hormones such as progesterone, mineralo- and gluco-corticoids, estrogens, and androgens. Its subcellular localization in steroidogenic tissues is usually considered to be mainly microsomal; however, 3 beta...

The enzyme 3 beta-hydroxysteroid dehydrogenase isomerase (3 beta-HSD/I) is an essential step in the biosynthesis of steroid such as progesterone, mineralo- and gluco-corticoids, estrogens and androgens in steroidogenic tissues. It is considered to be mainly localized in microsomes; however, 3 beta-HSD/I activity has also been described to be associ...

The formation of 4-ene-3-ketosteroids from 3 beta-hydroxy-5-ene precursors is an obligatory step in the biosynthesis of hormonal steroids such as glucocorticoids, mineralocorticoids, estrogens and androgens. In the adrenal cortex, pregnenolone, 17 alpha-hydroxy-pregnenolone and dehydroisoandrosterone are converted to progesterone, 17 alpha-hydroxy-...