Publications by authors named "Hélène Vanacker"

27 Publications

  • Page 1 of 1

PARP-inhibitors in epithelial ovarian cancer: Actual positioning and future expectations.

Cancer Treat Rev 2021 Sep 15;99:102255. Epub 2021 Jul 15.

Centre Léon Bérard, Lyon, France; University Claude Bernard Lyon 1, France. Electronic address:

Poly-(ADP)-ribose polymerase inhibitors (PARPi) are a class of oral anticancer drugs first developed as "synthetically lethal" in cancers harboring BRCA1/BRCA2 inactivating mutations. In high-grade serous or endometrioid ovarian cancers (HGOC), PARPi demonstrated benefit as maintenance therapy in relapsing BRCA-mutated and non-mutated tumors. Recently, they extended their indications to frontline maintenance therapy. This review summarizes the current place of PARPi (i) as maintenance or single agent in recurrent disease and (ii) frontline maintenance with different settings. We reviewed the course of biomarker identification, the challenge of overcoming resistance to PARPi and future combinations with targeted therapies, including anti-angiogenic, immune checkpoint inhibitors and DNA damage response inhibitors.
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http://dx.doi.org/10.1016/j.ctrv.2021.102255DOI Listing
September 2021

[New therapeutic strategies in HER2-positive breast cancer].

Bull Cancer 2021 Jun 15. Epub 2021 Jun 15.

Centre Léon-Bérard, département de cancérologie médicale, 28, rue Laennec, 69008 Lyon, France. Electronic address:

Breast cancer with HER2-amplification accounts for 20% of breast cancers. The management of patients has dramatically changed with the advent of anti-HER2 treatment, especially the monoclonal antibodies since 2000 in the metastatic and (neo)-adjuvant setting, leading to an improvement of patient outcomes. If therapeutic arsenal has been gradually enhanced with the targeting of HER receptors family, resistances to these treatments are observed, hence the development of new therapeutic strategies. This review provides an updated look of novel therapeutic strategies in HER2-positive breast cancer, as well as future perspectives, both in the adjuvant and metastatic setting.
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http://dx.doi.org/10.1016/j.bulcan.2021.04.015DOI Listing
June 2021

Poly(ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer.

Future Oncol 2021 06 17;17(18):2291-2304. Epub 2021 Mar 17.

Department of Medical Oncology, Centre Léon Bérard, 28 Prom. Léa et Napoléon Bullukian, Lyon, 69008, France.

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.
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http://dx.doi.org/10.2217/fon-2021-0059DOI Listing
June 2021

Overcoming resistance to PARP inhibitor in epithelial ovarian cancer, are we ready?

EBioMedicine 2020 Nov 7;61:103046. Epub 2020 Oct 7.

Centre Léon Bérard, 28 Prom. Léa et Napoléon Bullukian, Lyon 69008, France.

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http://dx.doi.org/10.1016/j.ebiom.2020.103046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553990PMC
November 2020

SRF Fusions Other Than With RELA Expand the Molecular Definition of SRF-fused Perivascular Tumors.

Am J Surg Pathol 2020 12;44(12):1725-1735

Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Cancer Research of Lyon, Centre Leon Berard.

Pericytic tumors encompass several entities sharing morphologic and immunohistochemical features. A subset of perivascular myoid tumors associated with the SRF-RELA fusion gene was previously described. Herein, we report a series of 13 tumors belonging to this group, in which we have identified new fusion genes by RNA-sequencing, thus expanding the molecular spectrum of this entity. All patients except 1 were children and infants. The tumors, frequently located in the head (n=8), had a mean size of 38 mm (range 10 to 150 mm) and were mostly (n=9) well-circumscribed. Exploration of the follow-up data (ranging from 3 to 68 mo) confirmed the benign behavior of these tumors. These neoplasms presented a spectrum of morphologies, ranging from perivascular patterns to myoid appearance. Tumor cells presented mitotic figures but without marked atypia. Some of these tumors could mimic sarcoma. The immunohistochemical profiles confirmed a pericytic differentiation with the expression of the smooth muscle actin and the h-caldesmon, as well as the frequent positivity for pan-cytokeratin. The molecular analysis identified the expected SRF-RELA fusion gene, in addition to other genetic alterations, all involving SRF fused to CITED1, CITED2, NFKBIE, or NCOA2. The detection of SRF-NCOA2 fusions in spindle cell rhabdomyosarcoma of the infant has previously been described, representing a risk of misdiagnosis, although the cases reported herein did not express MyoD1. Finally, clustering analyses confirmed that this group of SRF-fused perivascular myoid tumors forms a distinct entity, different from other perivascular tumors, spindle cell rhabdomyosarcomas of the infant, and smooth muscle tumors.
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http://dx.doi.org/10.1097/PAS.0000000000001546DOI Listing
December 2020

Therapeutic relevance of molecular screening program in patients with metastatic sarcoma: Analysis from the ProfiLER 01 trial.

Transl Oncol 2020 Dec 18;13(12):100870. Epub 2020 Sep 18.

Department of Medical Oncology, Léon Bérard Cancer Center, Lyon, France. Electronic address:

Background: Advanced sarcoma is a group of heterogeneous disease with poor prognosis and poor efficacy of medical treatment. They represent a promising group of tumors to assess molecular-based therapy (MBT) strategy.

Patients And Methods: Genomic profiles of patients with advanced sarcoma included in the ProfiLER program were established by NGS using a 69 genes panel and CGH array. A weekly molecular board reviewed genomic reports to select relevant genomic alterations and propose recommendations for MBT.

Results: A genomic profile was available for 158 of 164 patients. At least 1 relevant genomic alteration was reported for 106 patients (67%), with frequent multiple alterations (68%). In total, 289 relevant genomic alterations were identified in 143 different genes; 139 homozygous deletions, 86 gene amplifications and 64 somatic mutations. The most frequently impacted genes were TP53, Rb1, CDKN2A, CDK4, MDM2, and PTEN. MBT was recommended for 47 patients and initiated for 13 patients. One objective response was observed for an angiosarcoma treated with pazopanib for FLT4 amplification; 4 patients had a stable disease, including a long-lasting 33 months stabilization.

Conclusion: Genomic profiling for advanced sarcoma is feasible, even for bone sarcoma. A small proportion of patients are eventually treated with MBT, similar to other tumor types. We could not demonstrate this strategy to be beneficial to patients. Our data suggest that molecular profiling should not be used in routine practice but warrants further exploration in clinical trials, focusing on sarcoma with complex genomic, and adding transcriptomic analysis to the copy number and mutational analyses.
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http://dx.doi.org/10.1016/j.tranon.2020.100870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509228PMC
December 2020

Molecular Classification of Endometrial Stromal Sarcomas Using RNA Sequencing Defines Nosological and Prognostic Subgroups with Different Natural History.

Cancers (Basel) 2020 Sep 11;12(9). Epub 2020 Sep 11.

Department of Medical Oncology, Centre Léon Bérard, 28 rue Laennec, 69008 Lyon, France.

A series of 42 patient tumors diagnosed as endometrial stromal sarcoma (ESS) based on the morphology but negative for and/or rearrangement in FISH was analyzed by RNA-sequencing. A chromosomal rearrangement was identified in 31 (74%) of the cases and a missense mutation in known oncogenes/tumor suppressor genes in 11 (26%). Cluster analyses on the expression profiles from this series together with a control cohort composed of five samples of low grade ESS harboring a fusion, one high grade ESS harboring a -ITD, two uterine tumors resembling ovarian sex cord tumors, two samples each of uterine leiomyoma and leiomyosarcomas and a series of -rearranged family of tumor ( = 8) indicated that tumors could be gather in three distinct subgroups: one mainly composed of -rearranged samples that contained seven ESS samples, one mainly composed of -fused ESS ( = 15) and the last composed of various molecular subtypes ( = 19). These three subgroups display different gene signatures, different in silico cell cycle scores and very different clinical presentations, natural history and survival (log-rank test, = 0.004). While fusion genes may be present in both high and low grade ESS, the high-grade presents with additional or gene mutations. RNAseq brings clinically relevant molecular classification, enabling the reclassification of diseases and the guidance of therapeutic strategy.
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http://dx.doi.org/10.3390/cancers12092604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563240PMC
September 2020

Novel therapeutic options for alveolar soft part sarcoma: antiangiogenic therapy, immunotherapy and beyond.

Curr Opin Oncol 2020 07;32(4):295-300

Department of Medical Oncology.

Purpose Of Review: Alveolar soft part sarcoma (ASPS) represent 0.5% of sarcomas, defining a rarest among rare malignancies. It affects young adults, displaying slow-growing mass of the thigh, head and neck, and trunk. Although quite indolent, a majority of cases displays an advanced disease with lung bone or central nervous system metastasis. Complete surgery is the cornerstone of localized ASPS, and advanced diseases poorly respond to chemotherapy. Here discuss recent progress in molecular characterization of ASPS and future prospects of therapeutic approaches.

Recent Findings: ASPS is characterized by a specific oncogenic translocation ASPSCR1-TFE3 that induce hepatocyte growth factor receptor (MET) overexpression, angiogenesis, and immunosuppression in the tumor microenvironment. These specific biological features have encouraged the successful exploration of MET inhibitors, antiangiogenic drugs, and immunotherapy. We reviewed the main tracks of ASPS biology and recent insights from targeted therapies is ASPS mainly driven tyrosine kinase inhibitors (especially antiangiogenics), immune-checkpoint inhibitors, and their combinations.

Summary: Overall, antiangiogenics and anti Programmed cell death 1/Programmed cell death ligand 1 therapies showed a significant activity in ASPS that warrants additional investigation through randomized trials to validate those results and through ancillary biological studies to better understand resistance mechanisms and biomarkers of response.
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http://dx.doi.org/10.1097/CCO.0000000000000652DOI Listing
July 2020

Rare ovarian tumors: an update on diagnosis and treatment.

Int J Gynecol Cancer 2020 06 26;30(6):879-887. Epub 2020 May 26.

Medical Oncology, Centre Leon Berard, Lyon, Rhône-Alpes, France

Rare ovarian cancers occur frequently. Almost half of ovarian malignancies relate to several different 'rare' histotypes, according to the World Health Organization. The most common tumors are epithelial tumors, including high grade serous carcinomas, the presumed 'frequent ovarian cancers', together with low grade serous, mucinous, endometrioid, clear cell, and carcinosarcomas. Sex cord stromal tumors and germ cell carcinomas define two other groups of different subtypes, and small cell carcinomas are an independent high grade subtype closely related to the family of rhabdoid tumors. All of these cancers are primary ovarian cancers, classified by the International Federation of Gynecology and Obstetrics. However, the tumor subtypes display various epidemiologic, clinical, pathological, prognostic, and therapeutic characteristics. Because of the scarcity of data, current understanding of each subtype is limited and treatment has generally been derived from the more common tumor types. The aim of this article is to review the current literature on rare ovarian malignancies.
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http://dx.doi.org/10.1136/ijgc-2020-001235DOI Listing
June 2020

Current role of poly(ADP-ribose) polymerase inhibitors: which poly(ADP-ribose) polymerase inhibitor and when?

Curr Opin Oncol 2019 09;31(5):394-403

Purpose Of Review: In the past few years, the advent of PARP inhibitors has been a revolution in the management of ovarian cancer. Patients harboring somatic or germ line BRCA1/2 mutations exhibit different clinical and treatment response behavior. The BRCA gene is involved in repairing DNA repair via homologous recombination, and mutation of this gene leads to homologous recombination deficiency (HRD).

Recent Findings: HRD constitutes a therapeutic opportunity for these patients, thanks to the development of poly(ADP-ribose) polymerase inhibitors (PARPi) in the late 2000s. Indeed, using PARPi in patients with HRD simultaneously compromises two mechanisms of DNA repair, resulting in synthetic lethality.

Summary: This breakthrough in clinical practice has raised remaining questions: which population will most benefit from PARPi? Are all ovarian cancers susceptible to synthetic lethal strategy? At which stage of ovarian cancer should PARPi be used? Is earlier always better? Are PARPi all equivalent? Which strategies are reasonable to overcome PARPi resistance? Which combination strategies should be efficient?
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http://dx.doi.org/10.1097/CCO.0000000000000557DOI Listing
September 2019

Redox Regulation of Monodehydroascorbate Reductase by Thioredoxin y in Plastids Revealed in the Context of Water Stress.

Antioxidants (Basel) 2018 Dec 6;7(12). Epub 2018 Dec 6.

Institute of Plant Sciences Paris-Saclay (IPS2), UMR Université Paris Sud-CNRS 9213-INRA 1403, Bât. 630, 91405 Orsay CEDEX, France.

Thioredoxins (TRXs) are key players within the complex response network of plants to environmental constraints. Here, the physiological implication of the plastidial y-type TRXs in Arabidopsis drought tolerance was examined. We previously showed that TRXs y1 and y2 have antioxidant functions, and here, the corresponding single and double mutant plants were studied in the context of water deprivation. TRX y mutant plants showed reduced stress tolerance in comparison with wild-type (WT) plants that correlated with an increase in their global protein oxidation levels. Furthermore, at the level of the main antioxidant metabolites, while glutathione pool size and redox state were similarly affected by drought stress in WT and plants, ascorbate (AsA) became more quickly and strongly oxidized in mutant leaves. Monodehydroascorbate (MDA) is the primary product of AsA oxidation and NAD(P)H-MDA reductase (MDHAR) ensures its reduction. We found that the extractable leaf NADPH-dependent MDHAR activity was strongly activated by TRX y2. Moreover, activity of recombinant plastid Arabidopsis MDHAR isoform (MDHAR6) was specifically increased by reduced TRX y, and not by other plastidial TRXs. Overall, these results reveal a new function for y-type TRXs and highlight their role as major antioxidants in plastids and their importance in plant stress tolerance.
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http://dx.doi.org/10.3390/antiox7120183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316508PMC
December 2018

Impact of a visual aid on discordance between physicians and family members about prognosis of critically ill patients.

Anaesth Crit Care Pain Med 2018 Jun 5;37(3):207-210. Epub 2017 Aug 5.

Service de Réanimation, Centre Hospitalier Roanne, 28, rue de Charlieu, 42328 Roanne, France. Electronic address:

Objective: This study aimed to evaluate the impact of a visual aid on the discordance about prognosis between physicians and family members.

Methods: The study was performed in a general intensive care department with two 6-bed units. In the unit A, family members could consult a visual aid depicting day by day the evolution of global, hemodynamic, respiratory, renal and neurological conditions of the patient on a 10-point scale. In the unit B, they only received oral medical information. On day 7 of the ICU stay, the physician and family members estimated the prognosis of the patient among four proposals (life threatened; steady state but may worsen; steady state, should heal; will heal). Then we compared the rate of discordance about prognosis between physicians and family members in the two units.

Results: Seventy-nine consecutive patients admitted in the intensive care department and still present at day 7, their family members and physicians, were enrolled. Patients in the two units were comparable in age, sex ratio, reason for admission, SAPS II at admission and SOFA score at day 7. In the unit A, physician-family members discordance about prognosis occurred for 12 out of 39 patients (31%) vs. 22 out of 40 patients (55%) in the unit B (P=0.04).

Conclusion: In our study, adding a visual aid depicting the evolution of the condition of critically ill patients day by day to classic oral information allowed the family to have an estimate of the prognosis less discordant with the estimate of the physician.
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http://dx.doi.org/10.1016/j.accpm.2017.05.006DOI Listing
June 2018

Glutathione oxidation in response to intracellular HO: Key but overlapping roles for dehydroascorbate reductases.

Plant Signal Behav 2017 08 7;12(8):e1356531. Epub 2017 Aug 7.

a Institute of Plant Sciences Paris-Saclay (IPS2), UMR 9213/UMR1403 , Université Paris-Sud, CNRS, INRA, Université d'Evry, Université Paris-Diderot, Sorbonne Paris-Cité , Bâtiment 630, Orsay , France.

Glutathione is a pivotal molecule in oxidative stress, during which it is potentially oxidized by several pathways linked to HO detoxification. We have investigated the response and functional importance of 3 potential routes for glutathione oxidation pathways mediated by glutathione S-transferases (GST), glutaredoxin-dependent peroxiredoxins (PRXII), and dehydroascorbate reductases (DHAR) in Arabidopsis during oxidative stress. Loss-of-function gstU8, gstU24, gstF8, prxIIE and prxIIF mutants as well as double gstU8 gstU24, gstU8 gstF8, gstU24 gstF8, prxIIE prxIIF mutants were obtained. No mutant lines showed marked changes in their phenotype and glutathione profiles in comparison to the wild-type plants in either optimal conditions or oxidative stress triggered by catalase inhibition. By contrast, multiple loss of DHAR functions markedly decreased glutathione oxidation triggered by catalase deficiency. To assess whether this effect was mediated directly by loss of DHAR enzyme activity, or more indirectly by upregulation of other enzymes involved in glutathione and ascorbate recycling, we measured expression of glutathione reductase (GR) and expression and activity of monodehydroascorbate reductases (MDHAR). No evidence was obtained that either GRs or MDHARs were upregulated in plants lacking DHAR function. Hence, interplay between different DHARs appears to be necessary to couple ascorbate and glutathione pools and to allow glutathione-related signaling during enhanced HO metabolism.
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http://dx.doi.org/10.1080/15592324.2017.1356531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5616140PMC
August 2017

Emerging Role of the Unfolded Protein Response in Tumor Immunosurveillance.

Trends Cancer 2017 07 6;3(7):491-505. Epub 2017 Jul 6.

Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de recherche en cancérologie de Lyon, Lyon, 69008, France. Electronic address:

Disruption of endoplasmic reticulum (ER) homeostasis results in ER stress and activation of the unfolded protein response (UPR). This response alleviates cell stress, and is activated in both tumor cells and tumor infiltrating immune cells. The UPR plays a dual function in cancer biology, acting as a barrier to tumorigenesis at the premalignant stage, while fostering cancer maintenance in established tumors. In infiltrating immune cells, the UPR has been involved in both immunosurveillance and immunosuppressive functions. This review aims to decipher the role of the UPR at different stages of tumorigenesis and how the UPR shapes the balance between immunosurveillance and immune escape. This knowledge may improve existing UPR-targeted therapies and the design of novel strategies for cancer treatment.
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http://dx.doi.org/10.1016/j.trecan.2017.05.005DOI Listing
July 2017

[Advanced luminal breast cancer (hormone receptor-positive, HER2 negative): New therapeutic options in 2015].

Bull Cancer 2015 Jun;102(6 Suppl 1):S47-52

Département de médecine, Centre Léon-Bérard, Lyon, France. Electronic address:

Despite improvements in early detection, surgery and systemic therapy, metastatic breast cancer remains a major cause of death. Luminal type breast cancers expressing hormone estrogen receptor (ER) or progesterone (PR) and without HER2 overexpression are generally sensitive to endocrine therapy, but raise the issue of the occurrence of resistance to treatment, particularly at metastatic stage. A better understanding of hormone resistance may guide the development of new therapeutics. New strategies aim at enhancing and prolonging of endocrine sensitivity, by optimizing existing schemes, or by combining an endocrine therapy with a targeted therapies specific to hormone resistance pathways: ER signaling, PI3K/AKT/mTOR and Cyclin Dependent Kinase (CDK). Key corners of 2014 include confirmation of benefit of high dose fulvestrant, and commercialization of everolimus as the first mTOR inhibitor in this indication. Other strategies are being tested dealing with new endocrine therapies or new molecular targets such as PI3K inhibitors, insulin-like growth factor receptor (IGF-R) and histone deacetylase (HDAC) inhibitors. Coming years may be fruitful and might radically change our way to treat these patients.
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http://dx.doi.org/10.1016/S0007-4551(15)31217-0DOI Listing
June 2015

New insights into the reduction systems of plastidial thioredoxins point out the unique properties of thioredoxin z from Arabidopsis.

J Exp Bot 2012 Nov 23;63(18):6315-23. Epub 2012 Oct 23.

Institut de Biologie des Plantes, UMR CNRS 8618, Saclay Plant Sciences, Univ Paris-Sud, 91405, Orsay cedex, France.

In plants, thioredoxins (TRX) constitute a large protein disulphide oxidoreductase family comprising 10 plastidial members in Arabidopsis thaliana and subdivided in five types. The f- and m-types regulate enzymes involved mainly in carbon metabolism whereas the x, y, and z types have an antioxidant function. The reduction of TRXm and f in chloroplasts is performed in the light by ferredoxin:thioredoxin reductase (FTR) that uses photosynthetically reduced ferredoxin (Fd) as a reductant. The reduction system of Arabidopsis TRXx, y, and z has never been demonstrated. Recently, a gene encoding an atypical plastidial NADPH-dependent TRX reductase (NTRC) was found. In the present study, gene expression analysis revealed that both reductases are expressed in all organs of Arabidopsis and could potentially serve as electron donors to plastidial TRX. This ability was tested in vitro either with purified NTRC in presence of NADPH or with a light-driven reconstituted system comprising thylakoids and purified Fd and FTR. The results demonstrate that FTR reduces the x and y TRX isoforms but not the recently identified TRXz. Moreover, the results show that NTRC cannot be an efficient alternative reducing system, neither for TRXz nor for the other plastidial TRX. The data reveal that TRXf, m, x, and y, known as redox regulators in the chloroplast, have also the ability to reduce TRXz in vitro. Overall, the present study points out the unique properties of TRXz among plastidial TRX.
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http://dx.doi.org/10.1093/jxb/ers283DOI Listing
November 2012

The transcription factor ABI4 Is required for the ascorbic acid-dependent regulation of growth and regulation of jasmonate-dependent defense signaling pathways in Arabidopsis.

Plant Cell 2011 Sep 16;23(9):3319-34. Epub 2011 Sep 16.

Centre for Plant Sciences, Faculty of Biology, University of Leeds, Leeds LS2 9JT, UK.

Cellular redox homeostasis is a hub for signal integration. Interactions between redox metabolism and the ABSCISIC ACID-INSENSITIVE-4 (ABI4) transcription factor were characterized in the Arabidopsis thaliana vitamin c defective1 (vtc1) and vtc2 mutants, which are defective in ascorbic acid synthesis and show a slow growth phenotype together with enhanced abscisic acid (ABA) levels relative to the wild type (Columbia-0). The 75% decrease in the leaf ascorbate pool in the vtc2 mutants was not sufficient to adversely affect GA metabolism. The transcriptome signatures of the abi4, vtc1, and vtc2 mutants showed significant overlap, with a large number of transcription factors or signaling components similarly repressed or induced. Moreover, lincomycin-dependent changes in LIGHT HARVESTING CHLOROPHYLL A/B BINDING PROTEIN 1.1 expression were comparable in these mutants, suggesting overlapping participation in chloroplast to nucleus signaling. The slow growth phenotype of vtc2 was absent in the abi4 vtc2 double mutant, as was the sugar-insensitive phenotype of the abi4 mutant. Octadecanoid derivative-responsive AP2/ERF-domain transcription factor 47 (ORA47) and AP3 (an ABI5 binding factor) transcripts were enhanced in vtc2 but repressed in abi4 vtc2, suggesting that ABI4 and ascorbate modulate growth and defense gene expression through jasmonate signaling. We conclude that low ascorbate triggers ABA- and jasmonate-dependent signaling pathways that together regulate growth through ABI4. Moreover, cellular redox homeostasis exerts a strong influence on sugar-dependent growth regulation.
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http://dx.doi.org/10.1105/tpc.111.090100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3203439PMC
September 2011

Thioredoxin targets in Arabidopsis roots.

Proteomics 2010 Jul;10(13):2418-28

IBBMC, CNRS UMR 8619, Univ Paris-Sud, Orsay, France.

The importance of redox-regulation in Arabidopsis thaliana roots has been investigated through the identification of the proteins interacting with thioredoxin (TRX), an ubiquitous thiol-disulfide reductase. We have applied a proteomic approach based on affinity chromatography on a monocysteinic mutant of plastidial y-type TRX used as a bait to trap putative partners in a crude extract of root proteins. Seventy-two proteins have been identified, functioning mainly in metabolism, detoxification and response to stress, protein processing and signal transduction. This study allowed us to isolate 24 putative new targets and to propose the mevalonic acid-dependent biosynthesis of isoprenoids as a new redox-mediated process. The redox-regulation of phenylpropanoid biosynthesis is also suggested, three enzymes of this pathway being retained on the column. We also provided experimental evidence that phenylammonia-lyase was enzymatically more active when reduced by TRXy in root crude extract. Among the high number of partners involved in defense against stress we isolated from the column, we focused on plastidial monodehydroascorbate reductase and showed that its activity was dramatically increased in vitro in the presence of DTT-reduced TRXy1 in root crude extracts. Our data strongly suggest that TRXy1 could be the physiological regulator of monodehydroascorbate reductase in root plastids.
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http://dx.doi.org/10.1002/pmic.200900835DOI Listing
July 2010

H2O2-activated up-regulation of glutathione in Arabidopsis involves induction of genes encoding enzymes involved in cysteine synthesis in the chloroplast.

Mol Plant 2009 Mar 27;2(2):344-56. Epub 2009 Feb 27.

Institut de Biotechnologie des Plantes, UMR CNRS 8618, Université de Paris Sud, 91405 Orsay cedex, France.

Glutathione is a key player in cellular redox homeostasis and, therefore, in the response to H(2)O(2), but the factors regulating oxidation-activated glutathione synthesis are still unclear. We investigated H(2)O(2)-induced glutathione synthesis in a conditional Arabidopsis catalase-deficient mutant (cat2). Plants were grown from seed at elevated CO(2) for 5 weeks, then transferred to air in either short-day or long-day conditions. Compared to cat2 at elevated CO(2) or wild-type plants in any condition, transfer of cat2 to air in both photoperiods caused measurable oxidation of the leaf glutathione pool within hours. Oxidation continued on subsequent days and was accompanied by accumulation of glutathione. This effect was stronger in cat2 transferred to air in short days, and was not linked to appreciable increases in the extractable activities of or transcripts encoding enzymes involved in the committed pathway of glutathione synthesis. In contrast, it was accompanied by increases in serine, O-acetylserine, and cysteine. These changes in metabolites were accompanied by induction of genes encoding adenosine phosphosulfate reductase (APR), particularly APR3, as well as a specific serine acetyltransferase gene (SAT2.1) encoding a chloroplastic SAT. Marked induction of these genes was only observed in cat2 transferred to air in short-day conditions, where cysteine and glutathione accumulation was most dramatic. Unlike other SAT genes, which showed negligible induction in cat2, the relative abundance of APR and SAT2.1 transcripts was closely correlated with marker transcripts for H(2)O(2) signaling. Together, the data underline the importance of cysteine synthesis in oxidant-induced up-regulation of glutathione synthesis and suggest that the chloroplast makes an important contribution to cysteine production under these circumstances.
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http://dx.doi.org/10.1093/mp/ssp002DOI Listing
March 2009

In vivo targets of S-thiolation in Chlamydomonas reinhardtii.

J Biol Chem 2008 Aug 5;283(31):21571-8. Epub 2008 Jun 5.

Institut de Biotechnologie des Plantes, UMR 8618, Bâtiment 630, Orsay cedex, France.

Glutathionylation is the major form of S-thiolation in cells. This reversible redox post-translational modification consists of the formation of a mixed disulfide between a free thiol on a protein and a molecule of glutathione. This recently described modification, which is considered to occur under oxidative stress, can protect cysteine residues from irreversible oxidation, and alter positively or negatively the activity of diverse proteins. This modification and its targets have been mainly studied in non-photosynthetic organisms so far. We report here the first proteomic approach performed in vivo on photosynthetically competent cells, using the eukaryotic unicellular green alga Chlamydomonas reinhardtii with radiolabeled [(35)S]cysteine to label the glutathione pool and diamide as oxidant. This method allowed the identification of 25 targets, mainly chloroplastic, involved in various metabolic processes. Several targets are related to photosynthesis, such as the Calvin cycle enzymes phosphoglycerate kinase and ribose-5-phosphate isomerase. A number of targets, such as chaperones and peroxiredoxins, are related to stress responses. The glutathionylation of HSP70B, chloroplastic 2-Cys peroxiredoxin and isocitrate lyase was confirmed in vitro on purified proteins and the targeted residues were identified.
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http://dx.doi.org/10.1074/jbc.M802331200DOI Listing
August 2008

Conditional oxidative stress responses in the Arabidopsis photorespiratory mutant cat2 demonstrate that redox state is a key modulator of daylength-dependent gene expression, and define photoperiod as a crucial factor in the regulation of H2O2-induced cell death.

Plant J 2007 Nov 17;52(4):640-57. Epub 2007 Sep 17.

Institut de Biotechnologie des Plantes, Université de Paris Sud XI, 91405 Orsay cedex, France.

Photorespiration is a light-dependent source of H(2)O(2) in the peroxisomes, where concentrations of this signalling molecule are regulated by catalase. Growth of Arabidopsis knock-out mutants for CATALASE2 (cat2) in ambient air caused severely decreased rosette biomass, intracellular redox perturbation and activation of oxidative signalling pathways. These effects were absent when cat2 was grown at high CO(2) levels to inhibit photorespiration, but were re-established following a subsequent transfer to air. Growth of cat2 in air at different daylengths revealed that photoperiod is a critical determinant of the oxidative stress response. Decreased growth was observed in 8-h, 12-h and 16-h photoperiods, but lesion development was dependent on long days. Experiments at different light fluence rates showed that cell death in cat2 was linked to long days and not to total light exposure or the severity of oxidative stress. Perturbed intracellular redox state and oxidative signalling pathway induction were more prominent in short days than in long days, as evidenced by glutathione status and induction of defence genes and oxidative stress-responsive transcripts. Similar daylength-dependent effects were observed in the response of mature plants transferred from short days in high CO(2) conditions to ambient air conditions. Prior growth of plants with short days in air alleviated the cat2 cell-death phenotype in long days. Together, the data reveal the influence of photoperiodic events on redox signalling, and define distinct photoperiod-dependent strategies in the acclimation versus cell-death decision in stress conditions.
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http://dx.doi.org/10.1111/j.1365-313X.2007.03263.xDOI Listing
November 2007

Thioredoxins, glutaredoxins, and glutathionylation: new crosstalks to explore.

Photosynth Res 2006 Sep 7;89(2-3):225-45. Epub 2006 Nov 7.

Institut de Biotechnologie des Plantes, Unité Mixte de Recherche 8618, Centre National de la Recherche Scientifique/Université Paris-Sud, Bâtiment 630, Orsay Cedex, 91405, France.

Oxidants are widely considered as toxic molecules that cells have to scavenge and detoxify efficiently and continuously. However, emerging evidence suggests that these oxidants can play an important role in redox signaling, mainly through a set of reversible post-translational modifications of thiol residues on proteins. The most studied redox system in photosynthetic organisms is the thioredoxin (TRX) system, involved in the regulation of a growing number of target proteins via thiol/disulfide exchanges. In addition, recent studies suggest that glutaredoxins (GRX) could also play an important role in redox signaling especially by regulating protein glutathionylation, a post-translational modification whose importance begins to be recognized in mammals while much less is known in photosynthetic organisms. This review focuses on oxidants and redox signaling with particular emphasis on recent developments in the study of functions, regulation mechanisms and targets of TRX, GRX and glutathionylation. This review will also present the complex emerging interplay between these three components of redox-signaling networks.
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http://dx.doi.org/10.1007/s11120-006-9096-2DOI Listing
September 2006

Redox regulation of peroxiredoxin and proteinases by ascorbate and thiols during pea root nodule senescence.

FEBS Lett 2006 Feb 23;580(5):1269-76. Epub 2006 Jan 23.

Crop Performance and Improvement Division, Rothamsted Research, West Common, Harpenden, Hertfordshire AL5 2JQ, UK.

Redox factors contributing to nodule senescence were studied in pea. The abundance of the nodule cytosolic peroxiredoxin but not the mitochondrial peroxiredoxin protein was modulated by ascorbate. In contrast to redox-active antioxidants such as ascorbate and cytosolic peroxiredoxin that decreased during nodule development, maximal extractable nodule proteinase activity increased progressively as the nodules aged. Cathepsin-like activities were constant throughout development but serine and cysteine proteinase activities increased during senescence. Senescence-induced cysteine proteinase activity was inhibited by cysteine, dithiotreitol, or E-64. Senescence-dependent decreases in redox-active factors, particularly ascorbate and peroxiredoxin favour decreased redox-mediated inactivation of cysteine proteinases.
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http://dx.doi.org/10.1016/j.febslet.2006.01.043DOI Listing
February 2006

Combined agronomic and physiological aspects of nitrogen management in wheat highlight a central role for glutamine synthetase.

New Phytol 2006 ;169(2):265-78

Laboratoire d' Androgenèse et Biotechnologie Végétale, Université de Picardie Jules Verne, 33 Rue saint-Leu, F-80039 Amiens Cedex, France.

In wheat the period of grain filling is characterized by a transition for all vegetative organs from sink to source status. To study this transition, the progression of physiological markers and enzyme activities representative of nitrogen metabolism was monitored from the vegetative stage to maturity in different leaf stages and stem sections of two wheat (Triticum aestivum) cultivars grown at high and low levels of N fertilization. In the two cultivars examined, we found a general decrease of the metabolic and enzyme markers occurred during leaf ageing, and that this decrease was enhanced when plants were N-limited. Both correlation studies and principal components analysis (PCA) showed that there was a strong relationship among total N, chlorophyll, soluble protein, ammonium, amino acids and glutamine synthetase (GS) activity. The use of a marker such as GS activity to predict the N status of wheat, as a function of both plant development and N availability, is discussed with the aim of selecting wheat genotypes with better N-use efficiency.
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http://dx.doi.org/10.1111/j.1469-8137.2005.01606.xDOI Listing
March 2006

Legume nodule senescence: roles for redox and hormone signalling in the orchestration of the natural aging process.

New Phytol 2005 Mar;165(3):683-701

UMR CNRS-UNSA-INRA IPMSV 400, Route des Chappes, BP167 06903 Sophia-Antipolis Cedex, France.

Research on legume nodule development has contributed greatly to our current understanding of plant-microbe interactions. However, the factors that orchestrate root nodule senescence have received relatively little attention. Accumulating evidence suggests that redox signals contribute to the establishment of symbiosis and senescence. Although degenerative in nature, nodule senescence is an active process programmed in development in which reactive oxygen species (ROS), antioxidants, hormones and proteinases have key roles. Nodules have high levels of the redox buffers, ascorbate and glutathione, which are important in the nodulation process and in senescence. These metabolites decline with N-fixation as the nodule ages but the resultant decrease in redox buffering capacity does not necessarily lead to enhanced ROS or oxidative stress. We propose models by which ROS and antioxidants interact with hormones such as abscisic acid in the orchestration of nodule senescence.
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http://dx.doi.org/10.1111/j.1469-8137.2004.01285.xDOI Listing
March 2005

Intercellular distribution of glutathione synthesis in maize leaves and its response to short-term chilling.

Plant Physiol 2004 Apr 26;134(4):1662-71. Epub 2004 Mar 26.

Crop Performance and Improvement Division, Rothamsted Research, Harpenden, Herts AL5 2JQ, United Kingdom.

To investigate the intercellular control of glutathione synthesis and its influence on leaf redox state in response to short-term chilling, genes encoding gamma-glutamylcysteine synthetase (gamma-ECS) and glutathione synthetase (GSH-S) were cloned from maize (Zea mays) and specific antibodies produced. These tools were used to provide the first information on the intercellular distribution of gamma-ECS and GSH-S transcript and protein in maize leaves, in both optimal conditions and chilling stress. A 2-d exposure to low growth temperatures (chill) had no effect on leaf phenotype, whereas return to optimal temperatures (recovery) caused extensive leaf bleaching. The chill did not affect total leaf GSH-S transcripts but strongly induced gamma-ECS mRNA, an effect reversed during recovery. The chilling-induced increase in gamma-ECS transcripts was not accompanied by enhanced total leaf gamma-ECS protein or extractable activity. In situ hybridization and immunolocalization of leaf sections showed that gamma-ECS and GSH-S transcripts and proteins were found in both the bundle sheath (BS) and the mesophyll cells under optimal conditions. Chilling increased gamma-ECS transcript and protein in the BS but not in the mesophyll cells. Increased BS gamma-ECS was correlated with a 2-fold increase in both leaf Cys and gamma-glutamylcysteine, but leaf total glutathione significantly increased only in the recovery period, when the reduced glutathione to glutathione disulfide ratio decreased 3-fold. Thus, while there was a specific increase in the potential contribution of the BS cells to glutathione synthesis during chilling, it did not result in enhanced leaf glutathione accumulation at low temperatures. Return to optimal temperatures allowed glutathione to increase, particularly glutathione disulfide, and this was associated with leaf chlorosis.
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http://dx.doi.org/10.1104/pp.103.033027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC419840PMC
April 2004

Interactions between biosynthesis, compartmentation and transport in the control of glutathione homeostasis and signalling.

J Exp Bot 2002 May;53(372):1283-304

Institut de Biotechnologie des Plantes, Bât 630 Université Paris VII, 91405 Orsay Cedex, France.

Glutathione has numerous roles in cellular defence and in sulphur metabolism. These functions depend or impact on the concentration and/or redox state of leaf glutathione pools. Effective function requires homeostatic control of concentration and redox state, with departures from homeostasis acting as signals that trigger adaptive responses. Intercellular and intracellular glutathione pools are linked by transport across membranes. It is shown that glutathione can cross the chloroplast envelope at rates similar to the speed of biosynthesis. Control of glutathione concentration and redox state is therefore due to a complex interplay between biosynthesis, utilization, degradation, oxidation/reduction, and transport. All these factors must be considered in order to evaluate the significance of glutathione as a signalling component during development, abiotic stress, or pathogen attack.
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http://dx.doi.org/10.1093/jexbot/53.372.1283DOI Listing
May 2002
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