scholarly journals SCAP/SREBPs are Central Players in Lipid Metabolism and Novel Metabolic Targets in Cancer Therapy

2018 ◽  
Vol 18 (6) ◽  
pp. 484-493 ◽  
Author(s):  
Xiang Cheng ◽  
Jianying Li ◽  
Deliang Guo
Keyword(s):  
Lipid Metabolism ◽  
Cancer Therapy ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Lipid Synthesis ◽  
Feedback Regulation ◽  
Negative Feedback Regulation ◽  
Expression Of Genes ◽  
New Findings

Lipid metabolism reprogramming emerges as a new hallmark of malignancies. Sterol regulatory element-binding proteins (SREBPs), which are central players in lipid metabolism, are endoplasmic reticulum (ER)-bound transcription factors that control the expression of genes important for lipid synthesis and uptake. Their transcriptional activation requires binding to SREBP cleavageactivating protein (SCAP) to translocate their inactive precursors from the ER to the Golgi to undergo cleavage and subsequent nucleus translocation of their NH2-terminal forms. Recent studies have revealed that SREBPs are markedly upregulated in human cancers, providing the mechanistic link between lipid metabolism alterations and malignancies. Pharmacological or genetic inhibition of SCAP or SREBPs significantly suppresses tumor growth in various cancer models, demonstrating that SCAP/SREBPs could serve as promising metabolic targets for cancer therapy. In this review, we will summarize recent progress in our understanding of the underlying molecular mechanisms regulating SCAP/SREBPs and lipid metabolism in malignancies, discuss new findings about SREBP trafficking, which requires SCAP N-glycosylation, and introduce a newly identified microRNA-29-mediated negative feedback regulation of the SCAP/SREBP pathway. Moreover, we will review recently developed inhibitors targeting the SCAP/SREBP pathway for cancer treatment.

scholarly journals Apelin-mediated deamidation modification of HMGA1 promotes tumorigenesis by enhancing SRBEP1 activity and Lipid Synthesis

2020 ◽  
Author(s):  
Li Zhang ◽  
Yihan Zhu ◽  
Ying Yang ◽  
Hong Bu ◽  
Hong Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lipid Metabolism ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Protein Complexes ◽  
Regulatory Element ◽  
Lipid Synthesis ◽  
High Mobility ◽  
Lung Cancer Cells ◽  
Abnormal Lipid Metabolism

Abstract Apelin is a ligand of the G protein-coupled receptor that promotes tumor growth in malignant cancers. However, the molecular mechanisms through which apelin promotes tumorigenesis are unknown. Here, we confirmed that apelin promotes tumorigenesis in lung cancer cells by increasing the synthesis of fatty acids, which induces abnormal lipid metabolism. Apelin interacts with high-mobility group A HMGA1 and mediates sterol-regulatory-element-binding protein 1 (SREBP1) activity, which is required for lung tumorigenesis and lipid metabolism. Deamidation modification of HMGA1 is regulated by apelin enhanced SRBEP1 activity and lipid synthesis. Moreover, deamidated HMGA1 can enhance the formation of the apelin-HMGA1-SREBP1 complexes and increases SREBP1 activity, which induces abnormal lipid metabolism. As an energy regulator, Apelin forms a multi-protein complexes with HMGA1 to increase of lung cancer cells viability. Our results indicate that apelin is important in lipid metabolism and cancer cell proliferation.

scholarly journals The diverse and unanticipated roles of histone deacetylase 9 in coordinating plant development and environmental acclimation

2020 ◽  
Vol 71 (20) ◽  
pp. 6211-6225
Author(s):  
Peter G H de Rooij ◽  
Giorgio Perrella ◽  
Eirini Kaiserli ◽  
Martijn van Zanten
Keyword(s):  
Histone Deacetylase ◽  
Plant Development ◽  
Transcriptional Activation ◽  
Plant Traits ◽  
Feedback Regulation ◽  
Molecular Networks ◽  
Environmental Biology ◽  
Negative Feedback Regulation ◽  
Lysine Residues ◽  
Histone Deacetylase 9

Abstract Plants tightly control gene transcription to adapt to environmental conditions and steer growth and development. Different types of epigenetic modifications are instrumental in these processes. In recent years, an important role for the chromatin-modifying RPD3/HDA1 class I HDAC HISTONE DEACETYLASE 9 (HDA9) emerged in the regulation of a multitude of plant traits and responses. HDACs are widely considered transcriptional repressors and are typically part of multiprotein complexes containing co-repressors, DNA, and histone-binding proteins. By catalyzing the removal of acetyl groups from lysine residues of histone protein tails, HDA9 negatively controls gene expression in many cases, in concert with interacting proteins such as POWERDRESS (PWR), HIGH EXPRESSION OF OSMOTICALLY RESPONSIVE GENES 15 (HOS15), WRKY53, ELONGATED HYPOCOTYL 5 (HY5), ABA INSENSITIVE 4 (ABI4), and EARLY FLOWERING 3 (ELF3). However, HDA9 activity has also been directly linked to transcriptional activation. In addition, following the recent breakthrough discovery of mutual negative feedback regulation between HDA9 and its interacting WRKY-domain transcription factor WRKY53, swift progress in gaining understanding of the biology of HDA9 is expected. In this review, we summarize knowledge on this intriguing versatile—and long under-rated—protein and propose novel leads to further unravel HDA9-governed molecular networks underlying plant development and environmental biology.

scholarly journals Effects on Liver Lipid Metabolism of the Naturally Occurring Dietary Flavone Luteolin-7-glucoside

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Carla Sá ◽  
Ana Rita Oliveira ◽  
Cátia Machado ◽  
Marisa Azevedo ◽  
Cristina Pereira-Wilson
Keyword(s):  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Regulatory Element ◽  
Lipid Lowering ◽  
Whole Body ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Hepatic Expression

Disruptions in whole-body lipid metabolism can lead to the onset of several pathologies such as nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs). The present study aimed at elucidating the molecular mechanisms behind the lipid-lowering effects of the flavone luteolin-7-glucoside (L7G) which we previously showed to improve plasma lipid profile in rats. L7G is abundant in plant foods of Mediterranean diet such as aromatic plants used as herbs. Results show that dietary supplementation with L7G for one week induced the expression of peroxisome proliferator-activated receptor-alpha (PPAR-α) and of its target gene carnitine palmitoyl transferase 1 (CPT-1) in rat liver. L7G showed a tendency to decrease the hepatic expression of sterol regulatory element-binding protein-1 (SREBP-1), without affecting fatty acid synthase (FAS) protein levels. Although SREBP-2 and LDLr mRNA levels did not change, the expression of HMG CoA reductase (HMGCR) was significantly repressed by L7G. L7G also inhibited this enzyme’sin vitroactivity in a dose dependent manner, but only at high and not physiologically relevant concentrations. These results add new evidence that the flavone luteolin-7-glucoside may help in preventing metabolic diseases and clarify the mechanisms underlying the beneficial health effects of diets rich in fruits and vegetables.

scholarly journals β-catenin/LEF-1 Transcription Complex is Responsible for the Transcriptional Activation of LINC01278

2020 ◽  
Author(s):  
Shaojian Lin ◽  
Weiwei Zhang ◽  
Ziwen Shi ◽  
Langping Tan ◽  
Yue Zhu ◽  
...  
Keyword(s):  
Western Blot ◽  
Signaling Pathway ◽  
Transcriptional Activation ◽  
Feedback Regulation ◽  
Luciferase Reporter ◽  
Regulation Mechanism ◽  
Putative Promoter ◽  
Negative Feedback Regulation ◽  
Pathway Activation ◽  
Rna Immunoprecipitation

Abstract Background: Our previous study shows that LINC01278 inhibits the development of papillary thyroid carcinoma (PTC) by regulating miR-376c-3p/DNM3 axis. However, the regulation mechanism of LINC01278 expression in PTC cells is still unclear. Methods: The luciferase reporter and ChIP assays were used to confirme the binding of LEF-1 to the putative promoter site of LINC01278. The RNA immunoprecipitation was used the enrichment of LINC01278 in β-catenin protein. Western blot was used to detected the expression of target proteins. Results: Firstly, the online PROMO algorithm determined a putative LEF-1 binding site on LINC01278 promoter. Then, the luciferase reporter and ChIP assays confirmed the binding of LEF-1 to the putative promoter site of LINC01278. Furthermore, the overexpression of β-catenin increased the binding of LEF-1 to the LINC01278 promoter, and the knockdown or overexpression of LEF-1 or β-catenin can affect the expression level of LINC01278. In addition, RNA immunoprecipitation showed that LINC01278 was enriched in β-catenin protein. RNA pulldown and western blot also confirmed that LINC01278 precipitated β-catenin in TPC-1 and BCPAP cells. Furthermore, the knockdown or overexpression of LINC01278 significantly affected the expression of β-catenin and targets of Wnt/β-catenin signaling pathway (CCND2, CyclinD1, MYC, and SOX4). Conclusion: In summary, we found the transcriptional activation of LINC01278 by the β-catenin/LEF-1 transcription factor, and the negative feedback regulation of LINC01278 on Wnt/β-catenin signaling pathway activation.

A novel Sp1-relatedciselement involved in intestinal alkaline phosphatase gene transcription

1999 ◽  
Vol 276 (4) ◽  
pp. G800-G807 ◽  
Author(s):  
Jeong H. Kim ◽  
Shufen Meng ◽  
Amy Shei ◽  
Richard A. Hodin
Keyword(s):  
Alkaline Phosphatase ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Gene Activation ◽  
Regulatory Region ◽  
Intestinal Alkaline Phosphatase ◽  
Mobility Shift ◽  
Sv40 Promoter

We have used sodium butyrate-treated HT-29 cells as an in vitro model system to study the molecular mechanisms underlying intestinal alkaline phosphatase (IAP) gene activation. Transient transfection assays using human IAP-CAT reporter genes along with DNase I footprinting were used to localize a critical cis element (IF-III) corresponding to the sequence 5′-GACTGGGCGGGGTCAAGATGGA-3′. Deletion of the IF-III element resulted in a dramatic reduction in reporter gene activity, and IF-III was shown to function in the context of a heterologous (SV40) promoter in a cell type-specific manner, further supporting its functional role in IAP transactivation. Electrophoretic mobility shift assays revealed that IF-III binds Sp1 and Sp3, but these factors comprise only a portion of the total nuclear binding and appear to mediate only a small portion of its transcriptional activity. IF-III does not correspond to any previously characterized regulatory region from other intestine-specific genes. We have thus identified a novel, Sp1-related cis-regulatory element in the human IAP gene that appears to play a role in its transcriptional activation during differentiation in vitro.

scholarly journals Gender and age effects on the expression of genes related to lipid metabolism in broiler’s liver

2018 ◽  
Vol 63 (No. 3) ◽  
pp. 103-109
Author(s):  
A. de Souza Khatlab ◽  
A.P. Del Vesco ◽  
E. Gasparino ◽  
A.R. de Oliveira Neto
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
Weight Gain ◽  
Feed Intake ◽  
Broiler Chickens ◽  
Fatty Acid Synthase ◽  
Lipid Synthesis ◽  
Gender Effect ◽  
Expression Of Genes ◽  
Gender And Age

Two experiments were conducted to assess gender (Experiment 1) and age (Experiment 2) effects on the expression of genes related to lipid metabolism in broiler chickens. The expression of fatty acid synthase (FAS), apolipoprotein A-I (APOA-I), apolipoprotein B (APOB), adiponectin (ADIPOQ), liver kinase B1 (LKB1), and AMP-activated protein kinase α-1 (AMPKα-1) genes was evaluated by qRT-PCR. In Experiment 1, we observed a gender effect on feed intake, as male broilers presented greater feed intake than females. Female broilers presented greater gene expression of FAS, and lower expression of ADIPOQ and AMPKα-1, than males. A gender effect was not observed for the gene expression of APOA-I, APOB, or LKB1. In Experiment 2, there was a significant age effect on feed intake and weight gain. Broilers 42 days of age presented greater feed intake and weight gain than 21-day-old birds. 21-day-old broilers showed greater expression of APOA-I, ADIPOQ, LKB1, and AMPKα-1, and lower APOB gene expression in the liver than 42-day-old broilers. Age had no effect on FAS gene expression. Our results show that the gender and age could act on the expression of genes related to lipid synthesis, such as FAS and APOB, and also on genes related to lipid oxidation, such as ADIPOQ, LKB1, and AMPK.

scholarly journals A homeodomain protein related to caudal regulates intestine-specific gene transcription.

1994 ◽  
Vol 14 (11) ◽  
pp. 7340-7351 ◽  
Author(s):  
E Suh ◽  
L Chen ◽  
J Taylor ◽  
P G Traber
Keyword(s):  
Gene Family ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Cell Lineage ◽  
Specific Gene ◽  
Homeodomain Protein ◽  
Evolutionarily Conserved ◽  
Early Developmental

The continually renewing epithelium of the intestinal tract arises from the visceral endoderm by a series of complex developmental transitions. The mechanisms that establish and maintain the processes of cellular renewal, cell lineage allocation, and tissue restriction and spatial assignment of gene expression in this epithelium are unknown. An understanding of the regulation of intestine-specific gene regulation may provide information on the molecular mechanisms that direct these processes. In this regard, we show that intestine-specific transcription of sucrase-isomaltase, a gene that is expressed exclusively in differentiated enterocytes, is dependent on binding of a tissue-specific homeodomain protein (mouse Cdx-2) to an evolutionarily conserved promoter element in the sucrase-isomaltase gene. This protein is a member of the caudal family of homeodomain genes which appear to function in early developmental events in Drosophila melanogaster, during gastrulation in many species, and in intestinal endoderm. Unique for this homeodomain gene family, we show that mouse Cdx-2 binds as a dimer to its regulatory element and that dimerization in vitro is dependent on redox potential. These characteristics of the interaction of Cdx-2 with its regulatory element provide for a number of potential mechanisms for transcriptional regulation. Taken together, these findings suggest that members of the Cdx gene family play a fundamental role both in the establishment of the intestinal phenotype during development and in maintenance of this phenotype via transcriptional activation of differentiated intestinal genes.

scholarly journals Mutant p53 Gain-of-Function: Role in Cancer Development, Progression, and Therapeutic Approaches

2021 ◽  
Vol 8 ◽  
Author(s):  
Eduardo Alvarado-Ortiz ◽  
Karen Griselda de la Cruz-López ◽  
Jared Becerril-Rico ◽  
Miguel Angel Sarabia-Sánchez ◽  
Elizabeth Ortiz-Sánchez ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Driving Forces ◽  
Mevalonate Pathway ◽  
Regulatory Element ◽  
Metabolic Reprogramming ◽  
Loss Of Function ◽  
Therapeutic Approaches ◽  
Gain Of Function ◽  
The Impact

Frequent p53 mutations (mutp53) not only abolish tumor suppressor capacities but confer various gain-of-function (GOF) activities that impacts molecules and pathways now regarded as central for tumor development and progression. Although the complete impact of GOF is still far from being fully understood, the effects on proliferation, migration, metabolic reprogramming, and immune evasion, among others, certainly constitute major driving forces for human tumors harboring them. In this review we discuss major molecular mechanisms driven by mutp53 GOF. We present novel mechanistic insights on their effects over key functional molecules and processes involved in cancer. We analyze new mechanistic insights impacting processes such as immune system evasion, metabolic reprogramming, and stemness. In particular, the increased lipogenic activity through the mevalonate pathway (MVA) and the alteration of metabolic homeostasis due to interactions between mutp53 and AMP-activated protein kinase (AMPK) and Sterol regulatory element-binding protein 1 (SREBP1) that impact anabolic pathways and favor metabolic reprograming. We address, in detail, the impact of mutp53 over metabolic reprogramming and the Warburg effect observed in cancer cells as a consequence, not only of loss-of-function of p53, but rather as an effect of GOF that is crucial for the imbalance between glycolysis and oxidative phosphorylation. Additionally, transcriptional activation of new targets, resulting from interaction of mutp53 with NF-kB, HIF-1α, or SREBP1, are presented and discussed. Finally, we discuss perspectives for targeting molecules and pathways involved in chemo-resistance of tumor cells resulting from mutp53 GOF. We discuss and stress the fact that the status of p53 currently constitutes one of the most relevant criteria to understand the role of autophagy as a survival mechanism in cancer, and propose new therapeutic approaches that could promote the reduction of GOF effects exercised by mutp53 in cancer.

A homeodomain protein related to caudal regulates intestine-specific gene transcription

1994 ◽  
Vol 14 (11) ◽  
pp. 7340-7351
Author(s):  
E Suh ◽  
L Chen ◽  
J Taylor ◽  
P G Traber
Keyword(s):  
Gene Family ◽  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Regulatory Element ◽  
Cell Lineage ◽  
Specific Gene ◽  
Homeodomain Protein ◽  
Evolutionarily Conserved ◽  
Early Developmental

The continually renewing epithelium of the intestinal tract arises from the visceral endoderm by a series of complex developmental transitions. The mechanisms that establish and maintain the processes of cellular renewal, cell lineage allocation, and tissue restriction and spatial assignment of gene expression in this epithelium are unknown. An understanding of the regulation of intestine-specific gene regulation may provide information on the molecular mechanisms that direct these processes. In this regard, we show that intestine-specific transcription of sucrase-isomaltase, a gene that is expressed exclusively in differentiated enterocytes, is dependent on binding of a tissue-specific homeodomain protein (mouse Cdx-2) to an evolutionarily conserved promoter element in the sucrase-isomaltase gene. This protein is a member of the caudal family of homeodomain genes which appear to function in early developmental events in Drosophila melanogaster, during gastrulation in many species, and in intestinal endoderm. Unique for this homeodomain gene family, we show that mouse Cdx-2 binds as a dimer to its regulatory element and that dimerization in vitro is dependent on redox potential. These characteristics of the interaction of Cdx-2 with its regulatory element provide for a number of potential mechanisms for transcriptional regulation. Taken together, these findings suggest that members of the Cdx gene family play a fundamental role both in the establishment of the intestinal phenotype during development and in maintenance of this phenotype via transcriptional activation of differentiated intestinal genes.

Perception and Signaling of Ultraviolet-B Radiation in Plants

2021 ◽  
Vol 72 (1) ◽  
Author(s):  
Roman Podolec ◽  
Emilie Demarsy ◽  
Roman Ulm
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Nuclear Gene ◽  
Feedback Regulation ◽  
Ultraviolet B ◽  
Photon Absorption ◽  
Annual Review ◽  
Publication Date ◽  
Negative Feedback Regulation ◽  
Nuclear Gene Expression

Ultraviolet-B (UV-B) radiation is an intrinsic fraction of sunlight that plants perceive through the UVR8 photoreceptor. UVR8 is a homodimer in its ground state that monomerizes upon UV-B photon absorption via distinct tryptophan residues. Monomeric UVR8 competitively binds to the substrate binding site of COP1, thus inhibiting its E3 ubiquitin ligase activity against target proteins, which include transcriptional regulators such as HY5. The UVR8–COP1 interaction also leads to the destabilization of PIF bHLH factor family members. Additionally, UVR8 directly interacts with and inhibits the DNA binding of a different set of transcription factors. Each of these UVR8 signaling mechanisms initiates nuclear gene expression changes leading to UV-B-induced photomorphogenesis and acclimation. The two WD40-repeat proteins RUP1 and RUP2 provide negative feedback regulation and inactivate UVR8 by facilitating redimerization. Here, we review the molecular mechanisms of the UVR8 pathway from UV-B perception and signal transduction to gene expression changes and physiological UV-B responses. Expected final online publication date for the Annual Review of Plant Biology, Volume 72 is May 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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