Repression Of Activity Research Articles

ASPECTOS JURÍDICO-LEGAIS DA BUSCA PESSOAL AMPARADA NO PROCEDIMENTO OPERACIONAL PADRÃO (POP) DA POLÍCIA MILITAR DO ESTADO DE GOIÁS (PM-GO)

The work of the security forces is part of the context of guaranteeing and protecting the common good, which includes the actions of a police approach, seen as an instrument that contributes both to the promotion and maintenance of public order, as it is a form of preventive or repressive action in the scope of public safety. The objective of the study is to identify and discuss how PM-GO prepares and trains its military police to carry out ostensive and preventive policing and guides them to implement the correct police approach in personal search in line with legal and legal aspects which prescribe respect for citizens’ rights. For its elaboration, qualitative exploratory research was used based on bibliographic review based on journal articles, course completion papers such as graduation monographs, master’s dissertations and doctoral theses that deal with the police approach in its legal, procedural and technical. The results obtained in the research show that police power is inherent to the administrative activity that has the power to act on the conduct or situations of individuals or people who may, directly or indirectly, jeopardize the interests of the community, that is, the common good. The study also explains that reason-based reasons are a condition for carrying out the police approach, characteristics present in the individual that led the police officer to believe that there is an illegal and criminal situation. The article’s conclusions are that the police approach is a practice considered legitimate, supported by the constitutional text, ordinary laws and doctrinal notebooks and that the institute of personal search, used in the routine of the military, during ostensive patrolling, is covered with subjective criteria, imposing on the public agent to act with discretion, relying only on their personal experience.

The ubiquitination degradation of KLF15 mediated by WSB2 promotes lipogenesis and progression of hepatocellular carcinoma via inhibiting PDLIM2 expression.

Krüppel-like factors15 (KLF15) is a cancer suppressor in many cancers. However, its precise function in the development of hepatocellular carcinoma (HCC) remains unclear. Lipogenesis is necessary for the development of HCC. This research aims to investigate the role of KLF15 in the regulation of hepatic lipid production and HCC progression. The binding relationships among genes were confirmed by ChIP, dual luciferase assays, and Co-IP. Lipogenesis was examined by oil red O staining. Triglyceride and cholesterol levels were measured through commercial kits. The effect of treatment on HCC cell viability, proliferation, migration, and invasion were assessed using CCK-8, clone formation, or transwell assays. A subcutaneous tumorigenic model was utilized to explore the effects of PDLIM2 in HCC in vivo. KLF15 were downregulated in human HCC tissues. KLF15 overexpression reduced lipid droplet production, suppressed the expression of genes associated with lipogenesis, and promoted cell proliferation, migration, and invasion. KLF15 suppressed the NF-κB pathway through transcriptional activation of PDLIM2. PDLIM2 knockdown attenuated the effect of KLF15 overexpression on HCC. WSB2 degraded KLF15 through ubiquitination to promote HCC lipogenesis and development. The ubiquitination degradation of KLF15 was mediated by WSB2, which led to transcriptional repression of PDLIM2 and further activation of the NF-κB pathway, ultimately promoting HCC lipogenesis and development.

Repressor MrERF4 and Activator MrERF34 Synergistically Regulate High Flavonol Accumulation Under UV-B Irradiation in Morella rubra Leaves.

Flavonols are important plant photoprotectants to defence UV-B irradiation, however, the underlying transcriptional regulatory mechanism of rapid flavonol accumulation in response to UV-B remains unknown. In this study, content of flavonols was significantly induced from 0.11 to 3.80 mg/g fresh weight by UV-B irradiation in leaves of Morella rubra seedlings. MrERF34 was identified as an activator that can regulate the expression of MrFLS2, and promoted flavonol biosynthesis with activator MrMYB12 under UV-B treatment. Transient overexpression of MrERF34 resulted in higher flavonol accumulation, while virus-induced gene silencing of MrERF34 reduced the content of flavonols in bayberry leaves. We further demonstrated that a repressor MrERF4 inhibited the expression of MrERF34 and MrMYB12 as well as MrFLS2 via ERF-associated-amphiphilic repression motif. Exposure to UV-B reduced the promoter activity and transcription of MrERF4, which weakened the inhibitory effect of MrERF4 on MrERF34, MrMYB12, and MrFLS2, leading to a tremendous accumulation of flavonols. Such inhibitory roles of MrERF4 in regulation of flavonol biosynthesis were further validated by transient overexpression in leaves of Nicotiana benthamiana and M. rubra. These findings enrich the synergistical regulatory mechanisms between repressor and activators in flavonol biosynthesis, and provide new insights into photoprotectants biosynthesis to mitigate UV-B stress in plants.

Supervised Screening of EGFR Inhibitors Validated through Computational Structural Biology Approaches.

One of the prominent challenges in breast cancer (BC) treatment is human epidermal growth factor receptor (EGFR) overexpression, which facilitates tumor proliferation and presents a viable target for anticancer therapies. This study integrates multiomics data to pinpoint promising therapeutic compounds and employs a machine learning (ML)-based similarity search to identify effective alternatives. We used BC cell line data from the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases and single-cell RNA sequencing (scRNA-seq) information that established afatinib as an efficacious candidate demonstrating superior IC50 values. Next, ML models, including support vector machine (SVM), artificial neural networks (ANN), and random forest (RF), were trained on ChEMBL data to classify compounds with similar activity to the reference drug as active or inactive. The promising candidates underwent computational structural biology assessments for their molecular interactions and conformational dynamics. Our findings indicate that compounds ChEMBL233324, ChEMBL233325, ChEMBL234580, and ChEMBL372692 exhibit potent repressive action against EGFR, underscoring their potential as active antibreast cancer agents.

Mechanical Disruption by Focused Ultrasound Re-sensitizes ER+ Breast Cancer Cells to Hormone Therapy

ObjectiveTamoxifen is the most used agent to treat estrogen receptor-positive (ER+) breast cancer (BC). While it decreases the risk of cancer recurrence by 50%, many patients develop resistance to this treatment, culminating in highly aggressive disease. Tamoxifen resistance comes from the repression of ER transcriptional activity that switches the cancer cells to proliferation via nonhormonal signaling pathways. Here, we evaluate a potential strategy to overcome tamoxifen resistance by focused ultrasound (FUS), a noninvasive approach for the mechanical excitation of cancer cells. MethodsResistant and nonresistant ER+ BC cells and xenografts from patients with ER+ BC were treated with tamoxifen, FUS or their combination. The apoptosis, proliferation rate, gene expression and activity of estrogen receptor, and morphological changes were measured in treated cells and tissues. ResultsFUS caused the mechanical disruption of tamoxifen-resistant BC cells that in turn led to the upregulation of ERα-encoding gene expression and long-term re-sensitization of the cells to tamoxifen. Patient-derived xenografts treated with Tamoxifen and FUS demonstrated a significant reduction in tumor viability and proliferation and a strong structural damage to tumor cells and extracellular matrix. ConclusionFUS can improve ER+ BC treatment by re-sensitizing the cancer cells to tamoxifen.

Epigenetic dysregulation of H19/IGF2 in hepatic cells exposed to toxic metal mixtures in vitro

Exposure to mixtures of toxic metals is known to cause adverse health effects through epigenetic alterations. Here we aimed to examine the unexplored area of aberrant DNA methylation in the H19/IGF2 domain following combined toxic metal exposure. An in vitro epigenotoxicity assay using the human normal liver epithelial cell line THLE-3 was conducted. When THLE-3 cells were exposed to specific concentrations of either organic arsenic or MeHgCl, an increase in the H19 lncRNA levels and a marked reduction in the IGF2 mRNA levels were observed. In contrast, combined exposures coupled with CdCl2 resulted in the transcriptional repression of H19 and transcriptional activation of IGF2. It should be noted that the correlation between the dysregulated expression of H19/IGF2 and the hypermethylated CpG sites within the H19 differentially methylated region (DMR) was statistically significant. Furthermore, we performed transcriptomic analysis of the hepatocytes exposed to toxic metal combinations indicating enrichment of pro-inflammatory and anti-proliferative pathways compared to the unexposed cells. Our results suggest that hazardous metal mixtures may trigger epigenetic aberrations at the H19/IGF2 locus. We propose that altered CpG methylation in the H19 DMR could be a candidate biomarker for hepatic epigenotoxicity, in part, due to environmental exposure.

The miR319-based repression of SlTCP2/LANCEOLATE activity is required for regulating tomato fruit shape.

Fruit morphogenesis is determined by the coordination of cell division and expansion, which are fundamental processes required for the development of all plant organs. Here, we show that the regulation of TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) LANCEOLATE (TCP2/LA) by miR319 is crucial for tomato fruit morphology. The loss of miR319 regulation in the semi-dominant La mutant led to a premature SlTCP2/LA expression during gynoecium patterning, which results in modified cell division during carpel development. As a consequence, La mutants exhibited elongated ovary and fruit shape, and a reduced number of ovules and seeds. Elongated fruit shape in La may be partially due to the SlTCP2/LA-mediated repression of OVATE activity in young floral buds. Further analysis showed that the de-repression of SlTCP2/LA decreases auxin responses in young floral buds by directly repressing SlYUCCA4 expression, but SlTCP2/LA also acts in parallel with ENTIRE (E) to orchestrate fruit morphology and seed production. Our study defines a novel miRNA-based molecular link between the domestication-associated OVATE gene and auxin responses. Given the striking variation in fruit morphology among members of the Solanaceae family, fine-tuning regulation of gene expression by miRNA coupled with modulation of auxin dynamics may be a common driver in the evolution of fruit shape diversity.

Soviet Partisans in Lithuania in 1941–1944: Aspects of Repressive (Terrorist) Activity

The article deals with the establishment of the Soviet armed underground in the years of the Nazi Germany occupation (1941–1944), revealing its complicated situation and reasons, predetermining its repressive activity aspects – the use of coercion and violence. The expression of those activity aspects, concrete attempts to effect terror acts (political assassinations) against the German occupational regime, Lithuanian administration officers, political and military figures are elucidated on the basis of archival sources. Soviet armed underground in Lithuania had the strong, many-sided and multiple repressive origin. In the spring of 1941–1942, the most important role in the organization of Soviet resistance belonged to the USSR NKGB–NKVD bodies. Already in July-August 1941, twelve NKGB–NKVD groups, 85 people, were sent to Lithuania for terrorist (also for intelligence and sabotage) actions. Those groups were not able to develop any activities in Lithuania, almost all participants of those groups perished. From the end of 1942, the Soviet partisan resistance was organized and guided by the Communist Party institutions, attempting to organize the Soviet underground on the broader political and social basis. The participants of the Soviet underground were: 1) groups sent from the Soviet rear; 2) Soviet prisoners of war; 3) Jews who avoided the holocaust; 4) Lithuanian (and of other countries) inhabitants of other nationalities, most of whom suffered the German repressions. On the eve of the war (1940), in the USSR-occupied and annexed Lithuania, no prerequisites and conditions existed for the Soviet underground activity, the majority of the population did not support it, its participants maintained their existence only by repressions, coercion and violence. Directives for terrorist actions were given from the leading centres in the Soviet rear. Soviet partisans prepared unsuccessfully actions against the high-rank German occupational regime officers (General Commissioner in Lithuania Adrian von Renteln, Vilnius Command Commissioner Horst Wulff, etc.), the organizer of the local Lithuanian detachment Gen. Povilas Plechavičius. On the initiative of the Lithuanian national underground and supported by its participants, the Soviet partisans in March 1944 in the Švenčionys County killed two German leading economic executives (Fritz Ohl and Ernest Heinemann). The article, on the basis of indirect sources, makes a presumption that special Soviet underground groups at the end of April 1944 near Kaunas murdered the high-rank Orthodox Church clergyman Sergyi (Voskresenski).

The co-receptor Neuropilin-1 enhances proliferation in inv(16) acute myeloid leukemia via VEGF signaling.

Oncogenic programs regulate the proliferation and maintenance of cancer stem cells, and can define pharmacologic dependencies. In acute myeloid leukemia (AML) with the chromosome inversion 16 (inv(16)), the fusion oncoproteinCBFβ::MYH11 regulates pathways associated with leukemia stem cell activity. Here we demonstrate that expression of Neuropilin-1 (NRP1) is regulated by the fusion oncoprotein, and promotes AML expansion. Mechanistically, we show that the NRP1 locus has open chromatin in inv(16) AML, and that CBFβ::MYH11 modulates the local function of the transcription factors ERG, GATA2 and RUNX1 to sustain NRP1 levels. We found that ERG activates NRP1 expression, and that CBFβ::MYH11 knockdown represses ERG expression, thereby allowing the repressive activity of GATA2/RUNX1 at three NRP1 enhancers. Functionally, we demonstrate that NRP1 enhances the expansion of leukemic cells in vitro and in mice, and that this activity is dependent on its VEGFR-associated FV/FVIII domain. Finally, we show that treatment with VEGF inhibitor axitinib reduces AML cell growth and delays median leukemia latency in vivo. Our findings reveal that the NRP1/VEGF axis mediates proliferation in inv(16) AML blasts, and suggest that targeting NRP1 function could be promising in combination AML therapy.

Los maestros contra la RAE. Obstáculos y enredos de la oficialización de la gramática escolar académica en España (1875-1900)

This work aims to study the main challenges that academic school grammar faced in Spain for its consolidation in classrooms from the time of the Restoration, when its texts (Compendio and Epítome) became official again for the teaching of the Spanish language in public schools. Our analysis focuses specifically on examining the various news, reviews, and articles found in the Spanish printed press, a representative textual sample, not only of how the issue is experienced in Spanish society, but also of the different attitudes and opinions of intellectuals of the time regarding the matter, especially from the teachers, which maintained strong resistance against the repression actions carried out by the government and the Academy itself for the maintenance (and expansion) of their privileges and the consolidation of their doctrine in the classrooms.

DRN facilitates WUS transcriptional regulatory activity by chromatin remodeling to regulate shoot stem cell homeostasis in Arabidopsis.

Shoot stem cells, harbored in the shoot apical meristem (SAM), play key roles during post-embryonic development of Arabidopsis and function as the origin of plant aerial tissues. Multiple transcription factors are involved in the sophisticated transcriptional regulation of stem cell homeostasis, with the WUSCHEL (WUS)/CLAVATA3 (CLV3) negative feedback loop playing a central role. WUS acts as a master regulator in maintaining stem cells through its transcriptional regulatory activity including repressive and activating abilities. Although the interaction between WUS and TOPLESS confers the repressive activity of WUS in transcriptional control, the mechanism by which WUS activates gene expression remains elusive. Here, we showed that DORNRÖSCHEN competitively interacts with WUS and disturbs the WUS homodimer, which recruits BRAHMA to activate CLV3 expression via nucleosome depletion for maintaining the stem cell pool.

Digital dissent: How Indonesian and Filipino journalists converge with virtual communities to face state repression

Online protest movements have facilitated researchers to access real-time data of microblogging, user metadata associated with accounts, message content, and enabled insights into complex links between social media use and protest movements. Employing emerging computational techniques and conventional qualitative approaches, this study examines the effectiveness of online protest movements in Indonesia and the Philippines. Simultaneously deployed, these protests were organized by journalist groups against repressive state actions that muzzled the press in these countries. The study compares the strategies of the two movements to illustrate the success factors in social media usage that bolstered the participation of the national and global publics, and marshalled international support.

Targeting ketone body metabolism in mitigating gemcitabine resistance.

Chemotherapy is often combined with surgery for muscle invasive and non-muscle invasive bladder cancer. However, 70% of the patients recur within 5 years. Metabolic reprogramming is an emerging hallmark in cancer chemoresistance. Here, we report a gemcitabine resistance mechanism which promotes cancer reprogramming via the metabolic enzyme, OXCT1. This mitochondrial enzyme, responsible for the rate-limiting step in β-hydroxybutyrate (βHB) catabolism, was elevated in muscle invasive disease and in chemo-resistant bladder cancer patients. Resistant orthotopic tumors presented an OXCT1-dependent rise in mitochondrial oxygen consumption rate, ATP, and nucleotide biosynthesis. In resistant bladder cancer, knocking out OXCT1 restored gemcitabine sensitivity, and administering the non-metabolizable βHB, enantiomer (S-βHB) only partially restored gemcitabine sensitivity. Suggesting an extra-metabolic role for OXCT1, multi-omics analysis of gemcitabine sensitive and resistant cells revealed an OXCT1-dependent signature with the transcriptional repressor, OVOL1, as a master regulator of epithelial differentiation. The elevation of OVOL1 target genes was associated with its cytoplasmic translocation and poor prognosis in a chemotherapy-treated BCa patient cohort. The knockout of OXCT1 restored OVOL1 transcriptional repressive activity by its nuclear translocation. Orthotopic mouse models of bladder cancer supported OXCT1 as a mediator of gemcitabine sensitivity through ketone metabolism and regulating cancer stem cell differentiation.

A REPULSA DA POPULAÇÃO QUANTO A CRACOLÂNDIA: O CAOS E A GERAÇÃO DE UM PROBLEMA SOCIAL

The present work aims to investigate a study on Cracolandia as a generating factor of a social problem, in view of the absence of efficient policies of State intervention. In this work there is the objective of presenting the origin and evolution of Cracolandia, as well as bringing to light the responsibility of the State of São Paulo in the face of actions to confront this social problem. To discuss the theme, bibliographic research will be adopted, with emphasis on government news from the State of São Paulo, on data provided by the State Public Secretariat and on legislation relevant to the theme. In this way, it is perceived that the scenario in question is extremely degrading, and it is a situation directly linked to the omissive and repressive action of the State, as there are no efficient public policies that can solve this problem, but only measures that repress the homeless and drug addicts who live in Cracolandia.

Communicating State Repression to the International Community: A Case Study of How China Frames Its Policies in Xinjiang Online

Abstract Regimes and their proxies seek to legitimize overt state repression abroad to avoid economic and reputational costs. Yet, few scholars have studied the international dimension of repression image management. I examine how countries communicate their repressive actions to the international community depending on the audience. Framing repression as a legitimate response to a credible threat (threat strategy) is more likely when communicating with countries facing higher levels of domestic threat. But due to in-group favoritism, when addressing in-group audiences of the repressed, governments are more likely to frame repression as necessary to protect the repressed (benevolent rule strategy). To test these claims, I collect 82,011 tweets about activities in Xinjiang published by eighty-eight Chinese diplomatic accounts from 2014 to 2020. The results suggest that regimes change their repression image management strategies depending on the audience. Chinese government accounts in countries with higher levels of domestic conflict are more likely to use the threat strategy than those in countries with lower levels of conflict, while those in countries with a similar in-group to Xinjiang (Muslim countries) are more likely to use the benevolent rule strategy than those in out-group states. This expands our understanding of the communication strategies of human rights-abusing regimes.

Fpa (YlaN) is an iron(II) binding protein that functions to relieve Fur-mediated repression of gene expression in Staphylococcus aureus.

Iron (Fe) is a trace nutrient required by nearly all organisms. As a result of the demand for Fe and the toxicity of non-chelated cytosolic ionic Fe, regulatory systems have evolved to tightly balance Fe acquisition and usage while limiting overload. In most bacteria, including the mammalian pathogen Staphylococcus aureus, the ferric uptake regulator (Fur) is the primary transcriptional regulator controlling the transcription of genes that code for Fe uptake and utilization proteins. Fpa (formerly YlaN) was demonstrated to be essential in Bacillus subtilis unless excess Fe is added to the growth medium, suggesting a role in Fe homeostasis. Here, we demonstrate that Fpa is essential in S. aureus upon Fe deprivation. Null fur alleles bypassed the essentiality of Fpa. The absence of Fpa abolished the derepression of Fur-regulated genes during Fe limitation. Bioinformatic analyses suggest that fpa was recruited to Gram-positive bacteria and, once acquired, was maintained in the genome as it co-evolved with Fur. Consistent with a role for Fpa in alleviating Fur-dependent repression, Fpa and Fur interacted in vivo, and Fpa decreased the DNA-binding ability of Fur in vitro. Fpa bound Fe(II) in vitro using oxygen or nitrogen ligands with an association constant that is consistent with a physiological role in Fe homeostasis. These findings have led to a model wherein Fpa is an Fe(II) binding protein that influences Fur-dependent regulation through direct interaction.IMPORTANCEIron (Fe) is an essential nutrient for nearly all organisms. If Fe homeostasis is not maintained, Fe may accumulate in the cytosol, which can be toxic. Questions remain about how cells efficiently balance Fe uptake and usage to prevent overload. Iron uptake and proper metalation of proteins are essential processes in the mammalian bacterial pathogen Staphylococcus aureus. Understanding the gene products involved in the genetic regulation of Fe uptake and usage and the physiological adaptations that S. aureus uses to survive in Fe-depleted conditions provides insight into pathogenesis. Herein, we demonstrate that the DNA-binding activity of the ferric uptake regulator transcriptional repressor is alleviated under Fe limitation, but uniquely, in S. aureus, alleviation requires the presence of Fpa.

Penegakan Hukum terhadap Tindak Pidana Penadahan Kendaraan Bermotor di Kota Kupang

The crime of stealing a two-wheeled motor vehicle is one of the criminal offenses that is quite troubling in society in various regions of Indonesia and is ranked high compared to other cases. Motor vehicle theft is a simple crime that is very wrong when faced with the fact that today's perpetrators are professional and organized, the perpetrators of these crimes make motor vehicle theft a livelihood that generates a very large income. At this time, cases of motor vehicle seizures are rampant and even the impact is very detrimental to the community both in terms of economy and spirituality. This research is an empirical juridical research using interview guidelines for the Police, motor vehicle procurement perpetrators and the local community. The data collection technique uses interview guidelines and literature studies. The data used are primary data and secondary data. This research was conducted in Kupang City. Data processing and analysis techniques are carried out by editing, coding, classifying and tabulation data. The results of this study show that: (1) Law enforcement efforts carried out by the Police must be tightened using two ways of crime prevention, namely: Preventive Actions and Repressive Actions. (investigation and arrest of the perpetrator). (2) Factors that hinder the police in eradicating the crime of motor vehicle seizure are internal factors and external factors

AntimiR treatment corrects myotonic dystrophy primary cell defects across several CTG repeat expansions with a dual mechanism of action.

This study evaluated therapeutic antimiRs in primary myoblasts from patients with myotonic dystrophy type 1 (DM1). DM1 results from unstable CTG repeat expansions in the DMPK gene, leading to variable clinical manifestations by depleting muscleblind-like splicing regulator protein MBNL1. AntimiRs targeting natural repressors miR-23b and miR-218 boost MBNL1 expression but must be optimized for a better pharmacological profile in humans. In untreated cells, miR-23b and miR-218 were up-regulated, which correlated with CTG repeat size, supporting that active MBNL1 protein repression synergizes with the sequestration by CUG expansions in DMPK. AntimiR treatment improved RNA toxicity readouts and corrected regulated exon inclusions and myoblast defects such as fusion index and myotube area across CTG expansions. Unexpectedly, the treatment also reduced DMPK transcripts and ribonuclear foci. A leading antimiR reversed 68% of dysregulated genes. This study highlights the potential of antimiRs to treat various DM1 forms across a range of repeat sizes and genetic backgrounds by mitigating MBNL1 sequestration and enhancing protein synthesis.

Targeting circadian transcriptional programs through a cis-regulatory mechanism in triple negative breast cancer.

Circadian clock genes are emerging targets in many types of cancer, but their mechanistic contributions to tumor progression are still largely unknown. This makes it challenging to stratify patient populations and develop corresponding treatments. In this work, we show that in breast cancer, the disrupted expression of circadian genes has the potential to serve as biomarkers. We also show that the master circadian transcription factors (TFs) BMAL1 and CLOCK are required for the proliferation of metastatic mesenchymal stem-like (mMSL) triple-negative breast cancer (TNBC) cells. Using currently available small molecule modulators, we found that a stabilizer of cryptochrome 2 (CRY2), the direct repressor of BMAL1 and CLOCK transcriptional activity, synergizes with inhibitors of proteasome, which is required for BMAL1 and CLOCK function, to repress a transcriptional program comprising circadian cycling genes in mMSL TNBC cells. Omics analyses on drug-treated cells implied that this repression of transcription is mediated by the transcription factor binding sites (TFBSs) features in the cis-regulatory elements (CRE) of clock-controlled genes. Through a massive parallel reporter assay, we defined a set of CRE features that are potentially repressed by the specific drug combination. The identification of cis -element enrichment might serve as a new concept of defining and targeting tumor types through the modulation of cis -regulatory programs, and ultimately provide a new paradigm of therapy design for cancer types with unclear drivers like TNBC.

Upregulation of nuclear protein Hemgn by transcriptional repressor Gfi1 through repressing PU.1 contributes to the anti-apoptotic activity of Gfi1

Gfi1 is a transcriptional repressor that plays a critical role in hematopoiesis. The repressive activity of Gfi1 is mediated mainly by its SNAG domain that interacts with and thereby recruits the histone demethylase LSD1 to its target genes. An important function of Gfi1 is to protect hematopoietic cells against stress-induced apoptosis, which has been attributed to its participation in the posttranscriptional modifications of p53 protein, leading to suppression of p53 activity. In this study, we show that Gfi1 upregulated the expression of Hemgn, a nuclear protein, through a 16-bp promoter region spanning from +47 to +63 bp relative to the transcription start site (TSS), which was dependent on its interaction with LSD1. We further demonstrate that Gfi1, Ikaros and PU.1 bound to this 16-bp region. However, while Ikaros activated Hemgn and collaborated with Gfi1 to augment Hemgn expression, it was not required for Gfi1-mediated Hemgn upregulation. In contrast, PU.1 repressed Hemgn and inhibited Hemgn upregulation by Gfi1. Notably, PU.1 knockdown and deficiency, while augmenting Hemgn expression, abolished Hemgn upregulation by Gfi1. PU.1 (Spi-1) has been shown to be repressed by Gfi1. We show here that PU.1 repression by Gfi1 preceded and correlated well with Hemgn upregulation. Thus, our date strongly suggest that Gfi1 upregulates Hemgn by repressing PU.1. In addition, we demonstrate that Hemgn upregulation contributed to the anti-apoptotic activity of Gfi1 in a p53-independent manner.