scholarly journals ABA-induced cytoplasmic translocation of COP1 enhances ROS accumulation through the HY5-ABI5 pathway to modulate seed germination

2021 ◽  
Author(s):  
Qing-Bin Chen ◽  
Wenjing Wang ◽  
Yue Zhang ◽  
Qidi Zhan ◽  
Kang Liu ◽  
...  
Keyword(s):  
Seed Germination ◽  
Target Genes ◽  
Seedling Survival ◽  
Signal Transduction Pathway ◽  
Negative Regulator ◽  
Protein Levels ◽  
Aba Signal Transduction ◽  
Ros Accumulation ◽  
Light Signals ◽  
Cytoplasmic Translocation

Seed germination is a physiological process regulated by multiple factors. Abscisic acid (ABA) can inhibit seed germination to improve seedling survival under conditions of abiotic stress, and this process is often regulated by light signals. Constitutive Photomorphogenic 1 (COP1) is an upstream core repressor of light signals, and is involved in several ABA responses. Here, we demonstrate that COP1 is a negative regulator of the ABA-mediated inhibition of seed germination. Disruption of COP1 enhanced Arabidopsis seed sensitivity to ABA and increased ROS levels. In seeds, ABA induced the translocation of COP1 to the cytoplasm, resulting in enhanced ABA-induced ROS levels. Genetic evidence indicated that HY5 and ABI5 act downstream of COP1 in the ABA-mediated inhibition of seed germination. ABA-induced COP1 cytoplasmic localization increased HY5 and ABI5 protein levels in the nucleus, leading to increased expression of ABI5 target genes and ROS levels in seeds. Together, our results reveal that ABA-induced cytoplasmic translocation of COP1 activates the HY5-ABI5 pathway to promote the expression of ABA-responsive genes and the accumulation of ROS during ABA-mediated inhibition of seed germination. These findings enhance the role of COP1 in the ABA signal transduction pathway.

scholarly journals The microRNA miR-8 is a conserved negative regulator of Wnt signaling

2008 ◽  
Vol 105 (40) ◽  
pp. 15417-15422 ◽  
Author(s):  
Jennifer A. Kennell ◽  
Isabelle Gerin ◽  
Ormond A. MacDougald ◽  
Ken M. Cadigan
Keyword(s):  
Wnt Signaling ◽  
Signaling Pathway ◽  
Target Genes ◽  
Wnt Signaling Pathway ◽  
Negative Regulator ◽  
Animal Development ◽  
Protein Levels ◽  
Evolutionarily Conserved ◽  
Multiple Levels

Wnt signaling plays many important roles in animal development. This evolutionarily conserved signaling pathway is highly regulated at all levels. To identify regulators of the Wnt/Wingless (Wg) pathway, we performed a genetic screen in Drosophila. We identified the microRNA miR-8 as an inhibitor of Wg signaling. Expression of miR-8 potently antagonizes Wg signaling in vivo, in part by directly targeting wntless, a gene required for Wg secretion. In addition, miR-8 inhibits the pathway downstream of the Wg signal by repressing TCF protein levels. Another positive regulator of the pathway, CG32767, is also targeted by miR-8. Our data suggest that miR-8 potently antagonizes the Wg pathway at multiple levels, from secretion of the ligand to transcription of target genes. In addition, mammalian homologues of miR-8 promote adipogenesis of marrow stromal cells by inhibiting Wnt signaling. These findings indicate that miR-8 family members play an evolutionarily conserved role in regulating the Wnt signaling pathway.

scholarly journals Suppression of PTEN Expression by NF-κB Prevents Apoptosis

2004 ◽  
Vol 24 (3) ◽  
pp. 1007-1021 ◽  
Author(s):  
Krishna Murthi Vasudevan ◽  
Sushma Gurumurthy ◽  
Vivek M. Rangnekar
Keyword(s):  
Dna Binding ◽  
Target Genes ◽  
Negative Regulator ◽  
Pten Expression ◽  
Pten Gene ◽  
Transcription Activator ◽  
Potent Inducer ◽  
Protein Levels ◽  
Induced Apoptosis ◽  
Regulatory Loop

ABSTRACT NF-κB is a heterodimeric transcription activator consisting of the DNA binding subunit p50 and the transactivation subunit p65/RelA. NF-κB prevents cell death caused by tumor necrosis factor (TNF) and other genotoxic insults by directly inducing antiapoptotic target genes. We report here that the tumor suppressor PTEN, which functions as a negative regulator of phosphatidylinositol (PI)-3 kinase/Akt-mediated cell survival pathway, is down regulated by p65 but not by p50. Moreover, a subset of human lung or thyroid cancer cells expressing high levels of endogenous p65 showed decreased expression of PTEN that could be rescued by specific inhibition of the NF-κB pathway with IκB overexpression as well as with small interfering RNA directed against p65. Importantly, TNF, a potent inducer of NF-κB activity, suppressed PTEN gene expression in IKKβ+/+ cells but not in IKKβ−/− cells, which are deficient in the NF-κB activation pathway. These findings indicated that NF-κB activation was necessary and sufficient for inhibition of PTEN expression. The promoter, RNA, and protein levels of PTEN are down-regulated by NF-κB. The mechanism underlying suppression of PTEN expression by NF-κB was independent of p65 DNA binding or transcription function and involved sequestration of limiting pools of transcriptional coactivators CBP/p300 by p65. Restoration of PTEN expression inhibited NF-κB transcriptional activity and augmented TNF-induced apoptosis, indicating a negative regulatory loop involving PTEN and NF-κB. PTEN is, thus, a novel target whose suppression is critical for antiapoptosis by NF-κB.

scholarly journals AGL16 negatively modulates stress response to balance with growth

2021 ◽  
Author(s):  
Ping-Xia Zhao ◽  
Jing Zhang ◽  
Si-Yan Chen ◽  
Jie Wu ◽  
Jing-Qiu Xia ◽  
...  
Keyword(s):  
Stress Response ◽  
Seed Germination ◽  
Target Genes ◽  
Critical Role ◽  
Ion Homeostasis ◽  
Salt Resistance ◽  
Negative Regulator ◽  
Balance Growth ◽  
Wild Type ◽  
Enhanced Expression

ABSTRACTSensile plants constantly experience environmental stresses in nature. They must have evolved effective mechanisms to balance growth with stress response. Here we report the MADS-box transcription factor AGL16 acting as a negative regulator in stress response. Loss-of-AGL16 confers resistance to salt stress in seed germination, root elongation, and soil-grown plants, while elevated AGL16 expression confers the opposite phenotypes compared with wild type. However, the sensitivity to ABA in seed germination is inversely correlated with AGL16 expression level. Transcriptomic comparison revealed that the improved salt resistance of agl16 mutant was largely attributed to enhanced expression of stress responsive transcriptional factors and genes involved in ABA signaling and ion homeostasis. We further demonstrated that AGL16 directly binds to the CArG motifs in the promoter of HKT1;1, HsfA6a, and MYB102 and represses their expression. Genetic analyses with double mutants also support that HsfA6a and MYB102 are target genes of AGL16. Taken together, our results show that AGL16 acts as negative regulator transcriptionally suppressing key components in stress response and may play a critical role in balancing stress response with growth.

scholarly journals MAPK Signal Transduction Pathway Regulation: A Novel Mechanism of Rat HSC-T6 Cell Apoptosis Induced by FUZHENGHUAYU Tablet

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Qi Wang ◽  
Hongbo Du ◽  
Min Li ◽  
Yue Li ◽  
Shunai Liu ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Target Genes ◽  
Stellate Cell ◽  
Signal Transduction Pathway ◽  
Differentially Expressed ◽  
Mrna Levels ◽  
Protein Levels ◽  
Control Serum ◽  
Pathway Regulation ◽  
Induced Apoptosis

FUZHENGHUAYU Tablets have been widely used in the treatment of liver fibrosis in China. Here, we investigate the apoptotic effect of FUZHENGHUAYU Tablet in rat liver stellate cell line HSC-T6. HSC-T6 cells were incubated with control serum or drug serum from rats fed with 0.9% NaCl or FUZHENGHUAYU Tablet, respectively. Cells exposed to drug serum showed higher proportions of early and late apoptotic cells than controls. The mRNA levels of collagens I and III, TGF-β1 andα-SMA were reduced by drug serum compared to control serum. Differentially expressed mRNAs and miRNAs were analyzed by microarray and sequencing, respectively. We identified 334 differentially expressed mRNAs and also 60 GOs and two pathways related to the mRNAs. Seventy-five differentially expressed miRNAs were down-regulated by drug serum and 1963 target genes were predicted. 134 GOs up-regulated in drug serum group were linked to miRNA targets, and drug serum also regulated 43 miRNA signal transduction pathways. Protein levels were evaluated by Western blot. Drug serum down-regulated (phospho-SAPK/JNK)/(SAPK/JNK) and up-regulated phospho-p38/p38 ratios. The study showed that FUZHENGHUAYU Tablet induced apoptosis in rat HSC-T6 cells possibly in part by activating p38 and inhibiting SAPK/JNK.

scholarly journals ENAP1 retrains seed germination via H3K9 acetylation mediated positive feedback regulation of ABI5

PLoS Genetics ◽  
2021 ◽  
Vol 17 (12) ◽  
pp. e1009955
Author(s):  
Bo Zhao ◽  
Likai Wang ◽  
Zhengyao Shao ◽  
Kevin Chin ◽  
Daveraj Chakravarty ◽  
...  
Keyword(s):  
Seed Germination ◽  
Histone Acetylation ◽  
Molecular Mechanism ◽  
Positive Feedback ◽  
Target Genes ◽  
Feedback Regulation ◽  
Binding Activity ◽  
Promoter Regions ◽  
Protein Levels ◽  
H3k9 Acetylation

Histone acetylation is involved in the regulation of seed germination. The transcription factor ABI5 plays an essential role in ABA- inhibited seed germination. However, the molecular mechanism of how ABI5 and histone acetylation coordinate to regulate gene expression during seed germination is still ambiguous. Here, we show that ENAP1 interacts with ABI5 and they co-bind to ABA responsive genes including ABI5 itself. The hypersensitivity to ABA of ENAP1ox seeds germination is recovered by the abi5 null mutation. ABA enhances H3K9Ac enrichment in the promoter regions as well as the transcription of target genes co-bound by ENAP1 and ABI5, which requires both ENAP1 and ABI5. ABI5 gene is directly regulated by ENAP1 and ABI5. In the enap1 deficient mutant, H3K9Ac enrichment and the binding activity of ABI5 in its own promoter region, along with ABI5 transcription and protein levels are all reduced; while in the abi5-1 mutant, the H3K9Ac enrichment and ENAP1 binding activity in ABI5 promoter are decreased, suggesting that ENAP1 and ABI5 function together to regulate ABI5- mediated positive feedback regulation. Overall, our research reveals a new molecular mechanism by which ENAP1 regulates H3K9 acetylation and mediates the positive feedback regulation of ABI5 to inhibit seed germination.

scholarly journals A long hypoxia-inducible factor 3 isoform 2 is a transcription activator that regulates erythropoietin

2019 ◽  
Vol 77 (18) ◽  
pp. 3627-3642 ◽  
Author(s):  
Jussi-Pekka Tolonen ◽  
Minna Heikkilä ◽  
Marjo Malinen ◽  
Hang-Mao Lee ◽  
Jorma J. Palvimo ◽  
...  
Keyword(s):  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Negative Regulator ◽  
Luciferase Reporter ◽  
Transcription Activator ◽  
Promoter Regions ◽  
Α Subunit ◽  
Hypoxia Response ◽  
Protein Levels ◽  
Oxygen Homeostasis

AbstractHypoxia-inducible factor (HIF), an αβ dimer, is the master regulator of oxygen homeostasis with hundreds of hypoxia-inducible target genes. Three HIF isoforms differing in the oxygen-sensitive α subunit exist in vertebrates. While HIF-1 and HIF-2 are known transcription activators, HIF-3 has been considered a negative regulator of the hypoxia response pathway. However, the human HIF3A mRNA is subject to complex alternative splicing. It was recently shown that the long HIF-3α variants can form αβ dimers that possess transactivation capacity. Here, we show that overexpression of the long HIF-3α2 variant induces the expression of a subset of genes, including the erythropoietin (EPO) gene, while simultaneous downregulation of all HIF-3α variants by siRNA targeting a shared HIF3A region leads to downregulation of EPO and additional genes. EPO mRNA and protein levels correlated with HIF3A silencing and HIF-3α2 overexpression. Chromatin immunoprecipitation analyses showed that HIF-3α2 binding associated with canonical hypoxia response elements in the promoter regions of EPO. Luciferase reporter assays showed that the identified HIF-3α2 chromatin-binding regions were sufficient to promote transcription by all three HIF-α isoforms. Based on these data, HIF-3α2 is a transcription activator that directly regulates EPO expression.

scholarly journals The 40bp Indel Polymorphism rs150550023 in the MDM2 Promoter is Associated with Intriguing Shifts in Gene Expression in the p53-MDM2 Regulatory Hub

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3363
Author(s):  
Heidi Miedl ◽  
Bianca Dietrich ◽  
Klaus Kaserer ◽  
Martin Schreiber
Keyword(s):  
Breast Cancer ◽  
Genetic Risk ◽  
Target Genes ◽  
P53 Protein ◽  
Age At Onset ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Breast Cancer Patients ◽  
Indel Polymorphism ◽  
Protein Levels

Most low-penetrance genetic risk factors for cancer are located in noncoding regions, presumably altering the regulation of neighboring genes. The poorly characterized Indel polymorphism rs150550023 (rs3730485; del1518) in the promoter of MDM2 (human homolog of mouse double minute 2) is a biologically plausible candidate genetic risk factor, which might influence the expression of MDM2, a key negative regulator of the central tumor suppressor p53. Here, we genotyped rs150550023 in a Central European hospital-based case–control study of 407 breast cancer patients and 254 female controls. mRNA levels of MDM2, p53, and the p53 target genes p21, BAX, and PERP were quantified with qRT-PCR, and p53 protein was assessed with immune histochemistry in ≈100 primary breast tumors with ascertained rs150550023 genotype. We found no evidence for an association of rs150550023 with the risk, age at onset, or prognosis of breast cancer. A possible synergism was observed with SNP309 in promoter P2 of MDM2. Mean mRNA levels of MDM2, p53, p21, and BAX were ≈1.5–3 fold elevated in TP53 wildtype tumors with the minor homozygous Del/Del genotype. However, systematic shifts in p53 protein levels or mutation rates were not observed, suggesting that the elevated p53 mRNA levels are due to regulatory feedback loops that compensate for the effects of rs150550023 on MDM2 expression.

scholarly journals TRAIL-receptor 2—a novel negative regulator of p53

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Anna Willms ◽  
Hella Schupp ◽  
Michelle Poelker ◽  
Alshaimaa Adawy ◽  
Jan Frederik Debus ◽  
...  
Keyword(s):  
Target Genes ◽  
P53 Protein ◽  
Nuclear Bodies ◽  
Negative Regulator ◽  
Trail Receptor ◽  
Wild Type ◽  
Protein Levels ◽  
Pml Nuclear Bodies ◽  
P53 Target Gene

AbstractTNF-related apoptosis-inducing ligand (TRAIL) receptor 2 (TRAIL-R2) can induce apoptosis in cancer cells upon crosslinking by TRAIL. However, TRAIL-R2 is highly expressed by many cancers suggesting pro-tumor functions. Indeed, TRAIL/TRAIL-R2 also activate pro-inflammatory pathways enhancing tumor cell invasion, migration, and proliferation. In addition, nuclear TRAIL-R2 (nTRAIL-R2) promotes malignancy by inhibiting miRNA let-7-maturation. Here, we show that TRAIL-R2 interacts with the tumor suppressor protein p53 in the nucleus, assigning a novel pro-tumor function to TRAIL-R2. Knockdown of TRAIL-R2 in p53 wild-type cells increases the half-life of p53 and the expression of its target genes, whereas its re-expression decreases p53 protein levels. Interestingly, TRAIL-R2 also interacts with promyelocytic leukemia protein (PML), a major regulator of p53 stability. PML-nuclear bodies are also the main sites of TRAIL-R2/p53 co-localization. Notably, knockdown or destruction of PML abolishes the TRAIL-R2-mediated regulation of p53 levels. In summary, our finding that nTRAIL-R2 facilitates p53 degradation and thereby negatively regulates p53 target gene expression provides insight into an oncogenic role of TRAIL-R2 in tumorigenesis that particularly manifests in p53 wild-type tumors.

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