scholarly journals Time-series expression profiling of sugarcane leaves infected withPuccinia kuehniireveals an ineffective defense system leading to susceptibility

2019 ◽  
Author(s):  
Fernando Henrique Correr ◽  
Guilherme Kenichi Hosaka ◽  
Sergio Gregorio Perez Gomez ◽  
Mariana Cicarelli Cia ◽  
Claudia Barros Monteiro Vitorello ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Defense Responses ◽  
Recognition System ◽  
Resistance Mechanisms ◽  
Initial Time ◽  
Infected Leaf ◽  
Regulatory Pathways ◽  
Time Points ◽  
Phenylpropanoid Biosynthesis

AbstractPuccinia kuehniiis an obligate biotrophic fungus that infects sugarcane leaves causing a disease called orange rust. It spread out to other countries resulting in reduction of crop yield since its first outbreak in Australia. One of the knowledge gaps of that pathosystem is to understand the molecular mechanisms altered in susceptible plants by the stress induced byP. kuehnii. Here we investigated changes in temporal expression of transcripts in pathways associated with the immune system. To achieve this purpose, we used RNA-Seq to analyze infected leaf samples collected at 0, 12, 24, 48 hours after inoculation (hai), 5 and 12 days after inoculation (dai). Ade novotranscriptome was assembled with preprocessed reads, filtering out potential fungal sequences to focus on plant transcripts. Differential expression analyses of adjacent time points revealed substantial changes at 12, 48 hai and 12 dai, coinciding with the events of spore germination, haustoria post-penetration and post-sporulation. During the first 24 hours, a lack of transcripts involved with resistance mechanisms was revealed by underrepresentation of hypersensitive and defense responses. However, two days after inoculation, upregulation of genes involved with immune response regulation provided evidence of some potential defense response. Events related to biotic stress and phenylpropanoid biosynthesis pathways were predominantly downregulated in the initial time points, but expression was later restored to basal levels. Similar waves of expression were apparent for sets of genes in photosynthesis and oxidative processes, whose initial repression could avoid production of signaling molecules. Their subsequent upregulation possibly restored carbohydrate metabolism, ensuring pathogen nutritional requirements were met. Our results support the hypothesis thatP. kuehniiinitially suppressed sugarcane genes involved in plant defense systems. Late overexpression of specific regulatory pathways also suggests the possibility of an inefficient recognition system by a susceptible sugarcane genotype.

scholarly journals Identification and characterization of genes frequently responsive to Xanthomonas oryzae pv. oryzae and Magnaporthe oryzae infections in rice

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Weiwen Kong ◽  
Li Ding ◽  
Xue Xia
Keyword(s):  
Disease Resistance ◽  
Magnaporthe Oryzae ◽  
Enrichment Analysis ◽  
Defense Responses ◽  
Resistance Mechanisms ◽  
Xanthomonas Oryzae ◽  
Transcriptional Reprogramming ◽  
Go Enrichment ◽  
Phenylpropanoid Biosynthesis ◽  
Rice Disease

Abstract Background Disease resistance is an important factor that impacts rice production. However, the mechanisms underlying rice disease resistance remain to be elucidated. Results Here, we show that a robust set of genes has been defined in rice response to the infections of Xanthomonas oryzae pv. oryzae (Xoo) and Magnaporthe oryzae (Mor). We conducted a comprehensive analysis of the available microarray data from a variety of rice samples with inoculation of Xoo and Mor. A set of 12,932 genes was identified to be regulated by Xoo and another set of 2709 Mor-regulated genes was determined. GO enrichment analysis of the regulated genes by Xoo or Mor suggested mitochondrion may be an arena for the up-regulated genes and chloroplast be another for the down-regulated genes by Xoo or Mor. Cytokinin-related processes were most frequently repressed by Xoo, while processes relevant to jasmonic acid and abscisic acid were most frequently activated by Xoo and Mor. Among genes responsive to Xoo and Mor, defense responses and diverse signaling pathways were the most frequently enriched resistance mechanisms. InterPro annotation showed the zinc finger domain family, WRKY proteins, and Myb domain proteins were the most significant transcription factors regulated by Xoo and Mor. KEGG analysis demonstrated pathways including ‘phenylpropanoid biosynthesis’, ‘biosynthesis of antibiotics’, ‘phenylalanine metabolism’, and ‘biosynthesis of secondary metabolites’ were most frequently triggered by Xoo and Mor, whereas ‘circadian rhythm-plant’ was the most frequent pathway repressed by Xoo and Mor. Conclusions The genes identified here represent a robust set of genes responsive to the infections of Xoo and Mor, which provides an overview of transcriptional reprogramming during rice defense against Xoo and Mor infections. Our study would be helpful in understanding the mechanisms of rice disease resistance.

scholarly journals Autophagy-dependent TOR reactivation drives fungal growth in living host rice cells

2021 ◽  
Author(s):  
Gang Li ◽  
Ziwen Gong ◽  
Nawaraj Dulal ◽  
Raquel O Rocha ◽  
Richard A Wilson
Keyword(s):  
Amino Acid ◽  
Plant Pathogens ◽  
Molecular Mechanisms ◽  
Membrane Integrity ◽  
Defense Responses ◽  
Infected Leaf ◽  
Growth Stages ◽  
Autophagic Flux ◽  
In Planta ◽  
Interfacial Membrane

Eukaryotic filamentous plant pathogens with biotrophic growth stages like the devastating hemibiotrophic rice blast fungus Magnaporthe oryzae grow for extended periods in living host plant cells without eliciting defense responses. M. oryzae elaborates invasive hyphae (IH) that grow in and between living rice cells while separated from host cytoplasm by plant-derived membrane interfaces. However, although critical to the plant infection process, the molecular mechanisms and metabolic strategies underpinning this intracellular growth phase are poorly understood. Eukaryotic cell growth depends on activated target-of-rapamycin (TOR) kinase signaling, which inhibits autophagy. Here, using live-cell imaging coupled with plate growth tests and RNAseq, proteomic, quantitative phosphoproteomics and metabolic approaches, we show how cycles of autophagy in IH modulate TOR reactivation via α-ketoglutarate to sustain biotrophic growth and maintain biotrophic interfacial membrane integrity in host rice cells. Deleting the M. oryzae serine-threonine protein kinase Rim15-encoding gene attenuated biotrophic growth, disrupted interfacial membrane integrity and abolished the in planta autophagic cycling we observe here for the first time in wild type. δrim15 was also impaired for glutaminolysis and depleted for α-ketoglutarate. α-ketoglutarate treatment of Δrim15- infected leaf sheaths remediated Δrim15 biotrophic growth. In WT, α-ketoglutarate treatment suppressed autophagy. α-ketoglutarate signaling is amino acid prototrophy- and GS-GOGAT cycle-dependent. We conclude that, following initial IH elaboration, cycles of Rim15-dependent autophagic flux liberate α-ketoglutarate - via the GS-GOGAT cycle - as an amino acid-sufficiency signal to trigger TOR reactivation and promote fungal biotrophic growth in nutrient-restricted host rice cells.

scholarly journals Comparative Transcriptome Analysis Uncovers Genes and Pathways Relating to Downy Mildew Resistance in Isabgol (Plantago ovata Forsk.)

2020 ◽  
Author(s):  
Manivel Ponnuchamy ◽  
Sandip Patel ◽  
Jincy Mathew ◽  
Jitendra Kumar ◽  
Nagaraja Reddy Rama Reddy
Keyword(s):  
Downy Mildew ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Control Mechanisms ◽  
Plantago Ovata ◽  
Cell Wall Degrading Enzymes ◽  
Transcriptional Responses ◽  
Molecular Pattern ◽  
Phenylpropanoid Biosynthesis ◽  
Effector Triggered Immunity

Abstract BackgroundIsabgol (Plantago ovata Forsk.) downy mildew (DM), caused by obligate oomycete pathogen Peronospora plantaginis Underwood., is the single most damaging disease of Isabgol. However, reports on the genes and pathways involved in mediating resistance are still unknown.ResultsIn the present study, transcriptomic analysis was carried out by next generation sequencing of DM infected and uninfected leaves of resistant and susceptible genotypes to understand the genetic mechanisms underlie the host-plant resistance. A total of 33.47 million reads were generated and de novo assembled and annotated. The assembly using Trinity yielded 38803, 40175, 45451 and 39533 non-redundant transcript contigs, respectively in susceptible infected, Susceptible uninfected, Resistant infected and resistant uninfected samples. More than 90% of coding DNA sequence (CDS) predicted were annotated using BLAST search. Isabgol transcriptome showed the highest similarity to Sesamum indicum (41-59%) followed by Erythranthe guttata (10-13%). Putative CDS encoding Pathogen associated Molecular Pattern (PAMP)-triggered immunity (PTI), Effector-Triggered Immunity (ETI), Cell wall degrading enzymes, Phytohormone signalling and Phenylpropanoid biosynthesis pathways involved in host-pathogen interaction were identified in addition to the identification of several candidate resistance (R) genes enriched in response to DM infection. We identified significantly differentially expressed genes (DEGs) genes; 6928 DEGs in resistant uninfected (RU) vs resistant infected (RI) of DPO-185 (resistant) genotype and 8779 susceptible uninfected (SU) vs susceptible infected (SI) of DPO-14 (susceptible) genotype. Expression of 11 genes involved in plant defense quantified accordingly using RT-qPCR.ConclusionsThis study for the first time provides the glimpse of transcriptional responses to the DM resistance in Isabgol. The genes and pathways will be helpful in further investigating the molecular mechanisms associated with DM disease resistance in Isabgol and to develop control mechanisms accordingly.

scholarly journals Transcriptome profiling in susceptible and tolerant rubber tree clones in response to cassiicolin Cas1, a necrotrophic effector from Corynespora cassiicola

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254541
Author(s):  
Sébastien Ribeiro ◽  
Philippe Label ◽  
Dominique Garcia ◽  
Pascal Montoro ◽  
Valérie Pujade-Renaud
Keyword(s):  
Hypersensitive Response ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Negative Impact ◽  
Rubber Tree ◽  
Defense Responses ◽  
Differentially Expressed ◽  
Corynespora Cassiicola ◽  
Pathogenesis Related Protein ◽  
Necrotrophic Effector

Corynespora cassiicola, a fungal plant pathogen with a large host range, causes important damages in rubber tree (Hevea brasiliensis), in Asia and Africa. A small secreted protein named cassiicolin was previously identified as a necrotrophic effector required for the virulence of C. cassiicola in specific rubber tree clones. The objective of this study was to decipher the cassiicolin-mediated molecular mechanisms involved in this compatible interaction. We comparatively analyzed the RNA-Seq transcriptomic profiles of leaves treated or not with the purified cassiicolin Cas1, in two rubber clones: PB260 (susceptible) and RRIM600 (tolerant). The reads were mapped against a synthetic transcriptome composed of all available transcriptomic references from the two clones. Genes differentially expressed in response to cassiicolin Cas1 were identified, in each clone, at two different time-points. After de novo annotation of the synthetic transcriptome, we analyzed GO enrichment of the differentially expressed genes in order to elucidate the main functional pathways impacted by cassiicolin. Cassiicolin induced qualitatively similar transcriptional modifications in both the susceptible and the tolerant clones, with a strong negative impact on photosynthesis, and the activation of defense responses via redox signaling, production of pathogenesis-related protein, or activation of the secondary metabolism. In the tolerant clone, transcriptional reprogramming occurred earlier but remained moderate. By contrast, the susceptible clone displayed a late but huge transcriptional burst, characterized by massive induction of phosphorylation events and all the features of a hypersensitive response. These results confirm that cassiicolin Cas1 is a necrotrophic effector triggering a hypersensitive response in susceptible rubber clones, in agreement with the necrotrophic-effector-triggered susceptibility model.

scholarly journals De Novo Transcriptome Assembly of Isatis indigotica at Reproductive Stages and Identification of Candidate Genes Associated with Flowering Pathways

2018 ◽  
Vol 143 (1) ◽  
pp. 56-66
Author(s):  
Yu Bai ◽  
Ying Zhou ◽  
Xiaoqing Tang ◽  
Yu Wang ◽  
Fangquan Wang ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Transcriptome Assembly ◽  
Orthologous Group ◽  
Rna Seq ◽  
Isatis Indigotica ◽  
Regulatory Pathways ◽  
Kegg Pathways ◽  
Bolting And Flowering

The appropriate timing of bolting and flowering is one of the keys to the reproductive success of Isatis indigotica. Several flowering regulatory pathways have been reported in plant species, but we know little about flowering regulatory in I. indigotica. In the present study, we performed RNA-seq and annotated I. indigotica transcriptome using RNA from five tissues (leaves, roots, flowers, fruit, and stems). Illumina sequencing generated 149,907,857 high-quality clean reads and 124,508 unigenes were assembled from the sequenced reads. Of these unigenes, 88,064 were functionally annotated by BLAST searches against the public protein databases. Functional classification and annotation assigned 55,991 and 23,072 unigenes to 52 gene ontology (GO) terms and 25 clusters of orthologous group (COG) categories, respectively. A total of 19,927 unigenes were assigned to 124 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and 80 candidate genes related to plant circadian rhythm were identified. We also identified a number of differentially expressed genes (DEG) and 91 potential bolting and flowering-related genes from the RNA-seq data. This study is the first to identify bolting and flowering-related genes based on transcriptome sequencing and assembly in I. indigotica. The results provide foundations for the exploration of flowering pathways in I. indigotica and investigations of the molecular mechanisms of bolting and flowering in Brassicaceae plants.

scholarly journals Differences in midgut transcriptomes between resistant and susceptible strains of Chilo suppressalis to Cry1C toxin

BMC Genomics ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Geng Chen ◽  
Yanhui Wang ◽  
Yanmin Liu ◽  
Fajun Chen ◽  
Lanzhi Han
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Sustainable Use ◽  
Resistance Management ◽  
Resistance Mechanisms ◽  
Chilo Suppressalis ◽  
Illumina Hiseq ◽  
Cry Toxins ◽  
Cry Toxin ◽  
Rice Pest

Abstract Background Chilo suppressalis is a widespread rice pest that poses a major threat to food security in China. This pest can develop resistance to Cry toxins from Bacillus thuringiensis (Bt), threatening the sustainable use of insect-resistant transgenic Bt rice. However, the molecular basis for the resistance mechanisms of C. suppressalis to Cry1C toxin remains unknown. This study aimed to identify genes associated with the mechanism of Cry1C resistance in C. suppressalis by comparing the midgut transcriptomic responses of resistant and susceptible C. suppressalis strains to Cry1C toxin and to provide information for insect resistance management. Results A C. suppressalis midgut transcriptome of 139,206 unigenes was de novo assembled from 373 million Illumina HiSeq and Roche 454 clean reads. Comparative analysis identified 5328 significantly differentially expressed unigenes (DEGs) between C. suppressalis Cry1C-resistant and -susceptible strains. DEGs encoding Bt Cry toxin receptors, aminopeptidase-P like protein, the ABC subfamily and alkaline phosphatase were downregulated, suggesting an association with C. suppressalis Cry1C resistance. Additionally, Cry1C resistance in C. suppressalis may be related to changes in the transcription levels of enzymes involved in hydrolysis, digestive, catalytic and detoxification processes. Conclusion Our study identified genes potentially involved in Cry1C resistance in C. suppressalis by comparative transcriptome analysis. The assembled and annotated transcriptome data provide valuable genomic resources for further study of the molecular mechanisms of C. suppressalis resistance to Cry toxins.

scholarly journals Molecular Analysis of Enzymes and Metabolites Regulated Under Drought Stress in the Wild Plant Senna (Cassia Angustifolia)

2016 ◽  
Vol 16 (2) ◽  
pp. 307-326
Author(s):  
Nadiah Al-Sulami ◽  
Ahmed Atef ◽  
Mohammed Al-Matary ◽  
Sherif Edris ◽  
Khalid M. Al-Ghamdi ◽  
...  
Keyword(s):  
Drought Stress ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Mitogen Activated Protein Kinase ◽  
Wild Plant ◽  
Allene Oxide ◽  
Time Points ◽  
Cassia Angustifolia ◽  
Kegg Analysis ◽  
In The Wild

This study aimed at studying differential presence of enzymes metabolites via KEGG analysis of trasncriptomes of the wild plant species senna (Cassia angustifolia Vahl.) due to watering. Senna is a shrub of the family Caesalpiniaceae with important applications in pharmaceuticals. Firstly, RNA-Seq datasets were produced by next-generation sequencing (NGS) of Illumina Miseq of leaf (day 1) in order to detect the influence of watering at day 2. Samples were harvested at three time points (e.g., dawn, midday and dusk) of the two days. de novo assembled datasets and number of annotated genes exceeded 2000 genes. As cluster analysis of gene expression almost showed no discrete differences at the transcriptome level due to watering within time points of dawn and dusk, the study focused mainly on those of the midday across the two days. KEGG analysis for genes whose differential expression between the two days was ≥5 FC resulted in a number of enzymes that were found repressed due to watering, thus likely participate in the molecular mechanisms utilized by the organism to adapt to the long-lasting drought stress. The recovered regulated metabolites and enzymes included abscisic acid (ABA) receptor PYL4 and PYL9, auxin response factor (ARF) 5 and 15, ARF (or Aux/IAA) proteins IAA7 and IAA14, indole-3-pyruvate (or flavin) monooxygenase, phosphoinositide phosphatase SAC1 and SAC6, pre-mRNA splicing factors 8, 8A, 19, 40A and ISY1, and serine/arginine-rich splicing regultors SCL33, RS31 and RS34. The two pathways tryptophan metabolism and plant hormone signal transduction likely crosstalk in senna (C. angustifolia) towards the maintenance of normal growth under adverse condition. Many other regulated metabolites and proteins in senna (C. angustifolia) including brassinosteroid, heat shock protein 95s, ATPase, several protein kinases such as mitogen-activated protein kinase (MAPK) and cytochrome c oxidase. Other enzymes include phospholipase C2 and allene oxide cyclase as well as isochorismate pathway were also regulated in senna (C. angustifolia). In conclusion, we think that we have scoped the light on the possible regulated metabolites under drought stress that might confer drought stress tolerance in the wild plant senna (C. angustifolia).

Changes in Transcriptome and Gene Expression in Sogatella furcifera (Hemiptera: Delphacidae) in Response to Cycloxaprid

2020 ◽  
Author(s):  
Jian-Xue Jin ◽  
Zhao-Chun Ye ◽  
Dao-Chao Jin ◽  
Feng-Liang Li ◽  
Wen-Hong Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Sequences ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Virus Transmission ◽  
Resistance Mechanisms ◽  
Amino Acid Sequences ◽  
Coding Region ◽  
Sogatella Furcifera ◽  
Neonicotinoid Insecticide

Abstract The white-backed planthopper, Sogatella furcifera (Horváth), causes substantial damage to crops by direct feeding or virus transmission, especially southern rice black-streaked dwarf virus, which poses a serious threat to rice production. Cycloxaprid, a novel cis-nitromethylene neonicotinoid insecticide, has high efficacy against rice planthoppers, including imidacloprid-resistant populations. However, information about the influence of cycloxaprid on S. furcifera (Hemiptera: Delphacidae) at the molecular level is limited. Here, by de novo transcriptome sequencing and assembly, we constructed two transcriptomes of S. furcifera and profiled the changes in gene expression in response to cycloxaprid at the transcription level. We identified 157,906,456 nucleotides and 131,601 unigenes using the Illumina technology from cycloxaprid-treated and untreated S. furcifera. In total, 38,534 unigenes matched known proteins in at least one database, accounting for 29.28% of the total unigenes. The number of coding DNA sequences was 28,546 and that of amino acid sequences in the coding region was 22,299. In total, 15,868 simple sequence repeats (SSRs) were identified. The trinucleotide repeats accounted for 45.1% (7,157) of the total SSRs and (AAG/CTT)n were the most frequent motif. There were 359 differentially expressed genes that might have been induced by cycloxaprid. There were 131 upregulated and 228 downregulated genes. Twenty-two unigenes might be involved in resistance against cycloxaprid, such as cytochrome P450, glutathione S-transferase (GST), acid phosphatase (ACP), and cadherin. Our study provides vital information on cycloxaprid-induced resistance mechanisms, which will be useful to analyze the molecular mechanisms of cycloxaprid resistance and may lead to the development of novel strategies to manage S. furcifera.

scholarly journals Analysis ofPolygala tenuifoliaTranscriptome and Description of Secondary Metabolite Biosynthetic Pathways by Illumina Sequencing

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Hongling Tian ◽  
Xiaoshuang Xu ◽  
Fusheng Zhang ◽  
Yaoqin Wang ◽  
Shuhong Guo ◽  
...  
Keyword(s):  
Secondary Metabolite ◽  
Illumina Sequencing ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Local Alignment ◽  
Biosynthetic Pathways ◽  
Molecular Biological Analysis ◽  
Phenylpropanoid Biosynthesis ◽  
Potential Applications ◽  
Pharmaceutical Industries

Radix polygalae, the dried roots ofPolygala tenuifoliaandP. sibirica, is one of the most well-known traditional Chinese medicinal plants. Radix polygalae contains various saponins, xanthones, and oligosaccharide esters and these compounds are responsible for several pharmacological properties. To provide basic breeding information, enhance molecular biological analysis, and determine secondary metabolite biosynthetic pathways ofP. tenuifolia, we applied Illumina sequencing technology and de novo assembly. We also applied this technique to gain an overview ofP. tenuifoliatranscriptome from samples with different years. Using Illumina sequencing, approximately 67.2% of unique sequences were annotated by basic local alignment search tool similarity searches against public sequence databases. We classified the annotated unigenes by using Nr, Nt, GO, COG, and KEGG databases compared with NCBI. We also obtained many candidates CYP450s and UGTs by the analysis of genes in the secondary metabolite biosynthetic pathways, including putative terpenoid backbone and phenylpropanoid biosynthesis pathway. With this transcriptome sequencing, future genetic and genomics studies related to the molecular mechanisms associated with the chemical composition ofP. tenuifoliamay be improved. Genes involved in the enrichment of secondary metabolite biosynthesis-related pathways could enhance the potential applications ofP. tenuifoliain pharmaceutical industries.

Anticancer Agents Based on Vulnerable Components in a Signalling Pathway

2020 ◽  
Vol 20 (10) ◽  
pp. 886-907 ◽  
Author(s):  
Ankur Vaidya ◽  
Shweta Jain ◽  
Sanjeev Sahu ◽  
Pankaj Kumar Jain ◽  
Kamla Pathak ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Dna Methyltransferase ◽  
Leucine Zipper ◽  
Molecular Mechanisms ◽  
Resistance Mechanisms ◽  
Sphingosine Kinase 2 ◽  
Family Protein ◽  
Rational Combination ◽  
Protein Kinase Akt ◽  
Parp 1

Traditional cancer treatment includes surgery, chemotherapy, radiotherapy and immunotherapy that are clinically beneficial, but are associated with drawbacks such as drug resistance and side effects. In quest for better treatment, many new molecular targets have been introduced in the last few decades. Finding new molecular mechanisms encourages researchers to discover new anticancer agents. Exploring the mechanism of action also facilitates anticipation of potential resistance mechanisms and optimization of rational combination therapies. The write up describes the leading molecular mechanisms for cancer therapy, including mTOR, tyrosine Wee1 kinase (WEE1), Janus kinases, PI3K/mTOR signaling pathway, serine/threonine protein kinase AKT, checkpoint kinase 1 (Chk1), maternal embryonic leucine-zipper kinase (MELK), DNA methyltransferase I (DNMT1), poly (ADP-ribose) polymerase (PARP)-1/-2, sphingosine kinase-2 (SK2), pan-FGFR, inhibitor of apoptosis (IAP), murine double minute 2 (MDM2), Bcl-2 family protein and reactive oxygen species 1 (ROS1). Additionally, the manuscript reviews the anticancer drugs currently under clinical trials.

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