• HIV
• HIV latency
• HIV nuclear export
• HIV transcription
• latency-promoting agents
• latency-reversing agents
• viral persistence

• 2023 FI-1 00207 Agència de Gestió d'Ajuts Universitaris i de Recerca
• 2020 BP 00046 Agència de Gestió d'Ajuts Universitaris i de Recerca
• PID2019-109870RB-I00 Ministerio de Ciencia e Innovación
• CB21/13/00063 Ministerio de Ciencia e Innovación
• 1 UM1 AI164561-01 National Institute of Allergy and Infectious Diseases
• 1P01AI178376-01 National Institute of Allergy and Infectious Diseases
• 101057100 EU HORIZON-HLTH-2021-DISEASE-04-07
• 101095606 EU HORIZON-HLTH-2021-DISEASE-04-07
• 202130-30-31-32 Fundació La Marató de TV3
• PROMETEO/2021/036, Spain Generalitat Valenciana

• AR
• ERα
• GR
• PR
• coregulators
• lysine methyltransferases
• methylation
• protein arginine methyltransferases
• protein demethylases
• steroid receptors

We has identified a founder homozygous E3_E4 del: 2870 bp deletion + 9 bp insertion in AGT gene encoding angiotensinogen responsible for autosomal recessive renal tubular dysgenesis (ARRTD) with nearly-fatal outcome. High-dose hydrocortisone therapy successfully rescued one patient with an increased serum Angiotensinogen (AGT), Ang I, and Ang II levels. The pathogenesis of ARRTD caused by this AGT mutation and the potential therapeutic effect of hydrocortisone were examined by in vitro functional studies. The expression of this truncated AGT protein was relatively low with a dose-dependent manner. This truncated mutation diminished the interaction between mutant AGT and renin. The truncated AGT also altered the glucocorticoid receptor (GR)-dependent transactivation, indicating that AGT may affect the development of proximal convoluted tubule by alteration of glucocorticoid-dependent transactivation. In hepatocytes, hydrocortisone increased the AGT level by accentuating the stability of mutant AGT and increasing its binding with renin. Therefore, hydrocortisone may exert the therapeutic effect through the enhanced stability and interaction with renin of truncated AGT in patients carrying this AGT mutation.

• angiotensinogen
• founder effect
• renal tubular dysgenesis
• rescue therapy

• Angiotensinogen/genetics
• Base Sequence
• Cell Line
• DNA, Complementary/genetics
• Genes, Recessive
• Humans
• Hydrocortisone/pharmacology
• Kidney/metabolism
• Kidney Tubules, Proximal/abnormalities
• Liver/metabolism
• Models, Biological
• Mutant Proteins/metabolism
• Mutation/genetics
• Protein Binding/drug effects
• Protein Stability/drug effects
• Receptors, Glucocorticoid/metabolism
• Renin/metabolism
• Transcriptional Activation/genetics
• Urogenital Abnormalities/genetics

• Endoplasmic reticulum stress
• MODY
• Mitochondrial dysfunction
• Monogenic forms of diabetes
• Neonatal diabetes mellitus
• Pancreatic β-cell
• Transcription factors
• tRNA methylation
• β-cell apoptosis
• β-cell dysfunction

• HIV latency
• HIV transcription
• yeast one-hybrid

Skeletal muscle wasting represents both a common phenotype of aging and a feature of pathological conditions such as chronic kidney disease (CKD). Although both clinical data and genetic experiments in mice suggest that hyperphosphatemia accelerates muscle wasting, the underlying mechanism remains unclear. Here, we showed that inorganic phosphate (Pi) dose-dependently decreases myotube size, fusion index, and myogenin expression in mouse C2C12 skeletal muscle cells. These changes were accompanied by increases in reactive oxygen species (ROS) production and Nrf2 and p62 expression, and reductions in mitochondrial membrane potential (MMP) and Keap1 expression. Inhibition of Pi entry, cytosolic ROS production, or Nrf2 activation reversed the effects of high Pi on Nrf2, p62, and myogenin expression. Overexpression of Nrf2 respectively increased and decreased the promoter activity of p62-Luc and myogenin-Luc reporters. Analysis of nuclear extracts from gastrocnemius muscles from mice fed a high-Pi (2% Pi) diet showed increased Nrf2 phosphorylation in sham-operated and 5/6 nephrectomized (CKD) mice, and both increased p62 phosphorylation and decreased myogenin expression in CKD mice. These data suggest that high Pi suppresses myogenic differentiation in vitro and promotes muscle atrophy in vivo through oxidative stress-mediated protein degradation and both canonical (ROS-mediated) and non-canonical (p62-mediated) activation of Nrf2 signaling.

• Nrf2
• hyperphosphatemia
• muscle wasting
• myogenic differentiation
• oxidative stress

In recent years, L-ascorbic acid (L-AA), or vitamin C, has been attracting attention as a potential anticancer drug that mediates hydrogen peroxide-induced oxidation and ten-eleven translocation 2-catalyzed DNA demethylation. However, the precise mechanism by which L-AA acts remains unclear. We examined the cytotoxic effects of L-AA or sodium ascorbate in human cervical carcinoma cells by assessing cell viability, expression of cell cycle-related mRNAs and proteins, and mitochondrial functions, and by performing flow cytometric analyses of cell cycle profiles, apoptosis, cell proliferation, and production of reactive oxygen species (ROS). We later tested the effects of ascorbates in combination with two first-line chemotherapeutic drugs, cisplatin, and doxorubicin. At pharmacological concentrations (1–10 mM), L-AA increased ROS levels; decreased levels of several cell cycle-related proteins, including p53, p21, cyclin D1, and phosphorylated histone 3 at serine residue 10; induced DNA damage, as indicated by changes in γH2A.x; decreased levels of the anti-oxidative transcription factor Nrf2; and increased levels of catalase, superoxide dismutase 1, and endoplasmic reticulum stress-related indicators, such as the p-eIF2α/eIF2α ratio and CHOP levels. L-AA also promoted cell proliferation and induced apoptosis and mitochondrial dysfunction. Finally, L-AA increased the susceptibility of HeLa cells to cisplatin and doxorubicin. These findings provide insight into how the adjustment of the cellular ROS status through L-ascorbate (L-AA or sodium ascorbate) administration could potentially synergistically enhance the efficacy of cancer therapies.

• ER stress
• L-ascorbic acid
• Nrf2
• p53
• reactive oxygen species

The zinc-finger protein which regulates apoptosis and cell cycle arrest 1 (Zac1), encoded by Plagl1 gene, is a seven-zinc-finger containing transcription factor belonging to the imprinted genome and is expressed in diverse types of embryonic and adult human tissues. Zac1 is postulated to be a tumor suppressor by inducing cell cycle arrest and apoptosis through interacting and modulating transcriptional activity of p53 as it was named. Correspondingly, the reduction or loss of Zac1 expression is associated with the incidence and progression of several human tumors, including cervical cancer, breast cancer, ovarian cancer, pituitary tumors, and basal cell carcinoma, implying the rationality of utilizing Zac1 expression as novel a biomarker for the evaluation of cervical cancer prognosis. However, to date, it has not been elucidated whether Zac1 expression is related to the prognosis of patients in clinical cervical cancer tumor samples. To address the questions outlined above, we report here a comprehensive investigation of Zac1 expression in biopsies of clinical cervical carcinoma. By analyzing Zac1 expression in various gene expression profiling of cervical cancer databases, we show the association between high Zac1 expression and poor prognosis of cervical cancer. Functional enrichment analysis showed that high Zac1 expression was associated with epithelial-mesenchymal transition (EMT), which was further observed in clinical characteristics and metastatic carcinoma samples using immunohistochemical staining. Correspondingly, hypomethylation of CpG island on Zac1 promoter was observed in samples with high Zac1 expression in cervical carcinoma. Finally, overexpression of Zac1 in a variety of cervical cancer cell lines increase their mesenchymal biomarker expression and migration, strengthening the correlation between cervical cancers with high Zac1 expression and metastasis in clinical. In summary, this research firstly revealed that identifying Zac1 expression or the methylation status of CpG site on Zac1 promoter may provide us with novel indicators for the evaluation of cervical cancer metastasis.

• chromatin
• glucocorticoid receptor
• post-translational modification
• steroid hormone receptors
• transcription factors
• transcriptional regulation

Differentiated embryo chondrocyte 1 (DEC1) is a helix-loop-helix transcription factor that directly binds to the class B E-box in target genes. DEC1 exerts both pro-survival and pro-apoptotic effects in a cell- and tissue-dependent manner. Its actions play role the progression of cancer remains unclear.

We first examined the functional roles of DEC1 using the transient promoter reporter assay. Then, the knockdown of DEC1 expression was performed with the short hairpin RNA strategy in HeLa and A2058 cancer cell lines to check the cell cycle and mitochondrial function profile using the flow cytometry and Seahorse assays. We later clarified the role of DEC1 in the tumorigenesis using the colony formation, anchorage-independent growth assay, and cellular proliferation analysis.

In the present study, we tested two guanide-containing drugs, metformin and phenformin, and found that both exhibit cytotoxicity against HeLa cervical carcinoma and A2058 melanoma cells. This effect was mediated, at least in part, through activation of the AMPK pathway; degradation of important cellular proteins, such as DEC1 and p53; and suppression of mitochondrial function, colony formation, and anchorage-independent cell proliferation. Our results further suggest that the cytotoxicity of metformin and phenformin reflect the impact of the repressive actions of DEC1 on gene expression, including DEC1 itself. This in turn suppresses both anchorage-independent growth and cell proliferation.

These findings provide several lines of evidence suggesting that DEC1 activity contributes to tumorigenicity and that the antitumor properties of biguanides reflect their ability to inhibit DEC1 functions.

• differentiated embryo chondrocyte 1
• metformin
• p53
• phenformin
• tumorigenesis

• Neocortical development
• Neural progenitor proliferation
• Neurogenesis
• Plag gene family
• Telencephalic patterning
• Zinc finger transcription factors

Nuclear hormone receptors (NRs) are evolutionarily conserved ligand-dependent transcription factors. They are essential for human life, mediating the actions of lipophilic molecules, such as steroid hormones and metabolites of fatty acid, cholesterol, and external toxic compounds. The C2H2-type zinc finger proteins (ZNFs) form the largest family of the transcription factors in humans and are characterized by multiple, tandemly arranged zinc fingers. Many of the C2H2-type ZNFs are conserved throughout evolution, suggesting their involvement in preserved biological activities, such as general transcriptional regulation and development/differentiation of organs/tissues observed in the early embryonic phase. However, some C2H2-type ZNFs, such as those with the Krüppel-associated box (KRAB) domain, appeared relatively late in evolution and have significantly increased family members in mammals including humans, possibly modulating their complicated transcriptional network and/or supporting the morphological development/functions specific to them. Such evolutional characteristics of the C2H2-type ZNFs indicate that these molecules influence the NR functions conserved through evolution, whereas some also adjust them to meet with specific needs of higher organisms. We review the interaction between NRs and C2H2-type ZNFs by focusing on some of the latter molecules.

• Broad-Complex
• Krüppel-associated box (KRAB)
• SCAN
• Tramtrack
• and Bric-a-brac (BTB)/poxvirus and zinc finger (POZ)
• coregulator
• evolution
• noncoding RNA

• HeLa
• IL-11
• IL-6
• osteoarthritis
• zac1

• Benzene
• DEHP
• GH
• PCB
• Pituitary adenoma
• Pollution
• Somatostatin receptor

• Animals
• Benzene/toxicity
• Cell Line, Tumor
• Cell Survival/drug effects
• Diethylhexyl Phthalate/toxicity
• Environmental Pollutants/toxicity
• Estrogens/genetics
• Estrogens/metabolism
• Gene Expression/drug effects
• Growth Hormone/metabolism
• Growth Hormone-Secreting Pituitary Adenoma/chemically induced
• Polychlorinated Biphenyls/toxicity
• Rats
• Signal Transduction/drug effects
• Somatostatin/genetics
• Somatostatin/metabolism

• Epigallocatechin-3-gallate
• External genital warts
• HPV
• Keratinocytes
• Proliferation

• Aurora kinase B
• G9a
• glucocorticoid receptor
• methylation
• phosphorylation

• atherosclerosis
• epigallocatechin-3-gallate
• foam cells
• macrophage
• oxidized low-density lipoprotein

• Catechin/analogs & derivatives
• Catechin/pharmacology
• Cell Line
• Cholesterol/metabolism
• Foam Cells/drug effects
• Foam Cells/metabolism
• Gene Expression/drug effects
• Humans
• Macrophages/drug effects
• Macrophages/metabolism
• NF-kappa B/genetics
• NF-kappa B/metabolism
• Receptors, Scavenger/genetics
• Receptors, Scavenger/metabolism

• Cancer
• Diabetes
• PLAGL1
• Tumor suppressor gene

• Pac1
• Zac1
• neocortex
• neuronal migration
• progenitor maturation

• Breast cancer
• Corepressors and transcriptional regulation
• Estrogen receptor
• PINX1

• Animals
• Breast Neoplasms/genetics
• Breast Neoplasms/metabolism
• COS Cells
• Cell Cycle Proteins
• Cell Line, Tumor
• Cell Proliferation
• Chlorocebus aethiops
• Estrogen Receptor alpha/chemistry
• Estrogen Receptor alpha/genetics
• Estrogen Receptor alpha/metabolism
• Female
• Gene Expression Regulation, Neoplastic
• HEK293 Cells
• Hep G2 Cells
• Humans
• MCF-7 Cells
• Promoter Regions, Genetic
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism

Neural stem cells (NSCs) and imprinted genes play an important role in brain development. On historical grounds, these two determinants have been largely studied independently of each other. Recent evidence suggests, however, that NSCs can reset select genomic imprints to prevent precocious depletion of the stem cell reservoir. Moreover, imprinted genes like the transcriptional regulator Zac1 can fine tune neuronal vs astroglial differentiation of NSCs. Zac1 binds in a sequence-specific manner to pro-neuronal and imprinted genes to confer transcriptional regulation and furthermore coregulates members of the p53-family in NSCs. At the genome scale, Zac1 is a central hub of an imprinted gene network comprising genes with an important role for NSC quiescence, proliferation and differentiation. Overall, transcriptional, epigenomic, and genomic mechanisms seem to coordinate the functional relationships of NSCs and imprinted genes from development to maturation, and possibly aging.

• Zac1
• Cell fate decisions
• Neural stem cells
• Genomic imprinting
• Igf2-H19
• Dlk1
• p57^Kip2
• Necdin
• Differentiation
• Imprinted gene networks

p53 is a major tumor suppressor that is inactivated in over 50% of human cancer types through either mutation or inactivating interactions with viral or cellular proteins. The uncertainties around the link between p53 status, therapeutic response, and outcome in cancer suggest that additional factors may be involved. p53 isoforms that are generated via the alternative splicing pathway may be promising candidates for further investigation.

In this study, we report one new p53 protein with two internally deleted regions, resulting in one deleted amino acid fragment (from amino acid residues 42 to 89) and one reading frame-shift region (from amino acid residues 90-120) compared to wild-type p53. The functional status of the new p53 protein, which has a defect in its proline-rich and N-terminal DNA-binding domains, was characterized as possessing an intact conformation, exhibiting no transactivation activity, exerting a dominant-negative effect and an interacting with a coactivator with an arginine methyltransferase activity.

Taken together, our findings provide valuable information about the structure and function of p53 for the regulation of transactivation activity and cellular protein-protein interactions. Furthermore, natural p53 isoforms will help us understand the functional roles of the p53 family and potential therapeutics for p53-dependent cancers.

• 17β-estradiol
• Adipose tissue
• Androgens
• DHT
• Dihydrotestosterone
• E2
• FABP-4
• GLUT-4
• GPD1
• HPLC–ESI-MS/MS
• PPARγ
• S14
• Spot14 (Thrsp)
• T
• Testosterone
• WAT
• ZAC1
• dihydrotestosterone
• fatty acid binding protein 4
• glucose transporter type 4
• glycerol 3-phosphate dehydrogenase 1
• high-performance liquid chromatography/electrospray ionization tandem mass spectrometry
• peroxisome proliferator activated receptor gamma
• testosterone
• white adipose tissue

• Adipose Tissue, White/drug effects
• Adipose Tissue, White/metabolism
• Aging
• Androgens/pharmacology
• Animals
• Cell Cycle Proteins/biosynthesis
• Down-Regulation
• Female
• Genes, Tumor Suppressor
• Male
• Orchiectomy
• Ovariectomy
• RNA, Messenger/metabolism
• Rats
• Rats, Wistar
• Testosterone/blood
• Testosterone/pharmacology
• Transcription Factors/biosynthesis

• Animals
• Diabetes Mellitus, Experimental/genetics
• Diabetes Mellitus, Experimental/immunology
• Diabetes Mellitus, Type 1/genetics
• Diabetes Mellitus, Type 1/immunology
• Female
• Gene Expression Profiling
• Genetic Association Studies
• Genetic Predisposition to Disease/genetics
• Humans
• Jurkat Cells
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred NOD
• T-Lymphocytes/metabolism

• Alleles
• Animals
• CCCTC-Binding Factor
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Chromatin/chemistry
• Chromatin/metabolism
• Chromosomal Proteins, Non-Histone/metabolism
• Chromosomes, Human, Pair 6
• DNA-Binding Proteins/genetics
• DNA-Binding Proteins/metabolism
• Female
• Genes, Tumor Suppressor
• Genomic Imprinting
• Genotype
• Humans
• Mice
• Microfilament Proteins/genetics
• Microfilament Proteins/metabolism
• Nerve Tissue Proteins/genetics
• Nerve Tissue Proteins/metabolism
• Placenta/metabolism
• Pregnancy
• Protein Isoforms/genetics
• Protein Isoforms/metabolism
• RNA, Messenger/genetics
• Repressor Proteins/metabolism
• Transcription Factors/genetics
• Cohesins

• GGP11122 Telethon

Cofactors are intimately involved in steroid-regulated gene expression. Two critical questions are (1) the steps at which cofactors exert their biological activities and (2) the nature of that activity. Here we show that a new mathematical theory of steroid hormone action can be used to deduce the kinetic properties and reaction sequence position for the functioning of any two cofactors relative to a concentration limiting step (CLS) and to each other. The predictions of the theory, which can be applied using graphical methods similar to those of enzyme kinetics, are validated by obtaining internally consistent data for pair-wise analyses of three cofactors (TIF2, sSMRT, and NCoR) in U2OS cells. The analysis of TIF2 and sSMRT actions on GR-induction of an endogenous gene gave results identical to those with an exogenous reporter. Thus new tools to determine previously unobtainable information about the nature and position of cofactor action in any process displaying first-order Hill plot kinetics are now available.

The cerebellum is composed of a diverse array of neuronal subtypes. Here we have used a candidate approach to identify Zac1, a tumor suppressor gene encoding a zinc finger transcription factor, as a new player in the transcriptional network required for the development of a specific subset of cerebellar nuclei and a population of Golgi cells in the cerebellar cortex.

We found that Zac1 has a complex expression profile in the developing cerebellum, including in two proliferating progenitor populations; the cerebellar ventricular zone and the external granular layer overlying posterior cerebellar lobules IX and X. Zac1 is also expressed in some postmitotic cerebellar neurons, including a subset of GABAergic interneurons in the medial cerebellar nuclei. Notably, GABAergic interneurons in the cerebellar nuclei are derived from the cerebellar ventricular zone, where Zac1 is also expressed, consistent with a lineage relationship between these two Zac1⁺ populations. Zac1 is also expressed in a small subset of cells in the posterior vermis, including some neurogranin-immunoreactive (NG⁺) Golgi cells, which, based on short-term birthdating, are derived from the EGL, where Zac1 is also expressed. However, Zac1⁺ cells and NG⁺ Golgi cells in the cerebellar cortex also display unique properties, as they are generated within different, albeit overlapping, time windows. Finally, consistent with the expression profile of Zac1, two conspicuous abnormalities were found in the cerebellum of Zac1 null mice: the medial cerebellar nuclei, and not the others, were significantly reduced in size; and the number of Golgi cells in cerebellar lobule IX was reduced by approximately 60% compared to wild-type littermates.

The data presented here indicate that the tumor suppressor gene Zac1 is expressed in a complex fashion in the developing cerebellum, including in two dividing progenitor populations and in specific subsets of postmitotic neurons, including Golgi cells and GABAergic neurons in the medial nuclei, which require Zac1 for their differentiation. We thus conclude that Zac1 is a critical regulator of normal cerebellar development, adding a new transcriptional regulator to the growing list of factors involved in generating neuronal diversity in the developing cerebellum.

• Animals
• Cell Cycle Proteins/genetics
• Cell Cycle Proteins/metabolism
• Fetus/metabolism
• Gene Expression
• Gene Expression Regulation, Developmental
• Genes, Tumor Suppressor
• Humans
• In Situ Hybridization
• Insulin-Secreting Cells/metabolism
• Mice
• Mice, Inbred C57BL
• Organ Specificity
• Pancreas/embryology
• Pancreas/metabolism
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism

The transcriptional activity of Nuclear hormone Receptors (NRs) is regulated by interaction with coactivator or corepressor proteins. Many of these cofactors have been shown to have a misregulated expression or to show a subcellular mislocalization in cancer cell lines or primary tumors. Therefore they can be factors involved in the process of oncogenesis.

We describe a novel NR coregulator, TACC1, which belongs to the Transforming Acidic Coiled Coil (TACC) family. The interaction of TACC1 with Thyroid Hormone Receptors (TR) and several other NRs has been shown in a yeast two-hybrid screen and confirmed by GST pulldown, colocalization and co-immunoprecipitation experiments. TACC1 interacts preferentially with unliganded NRs. In F9 cells, endogenous TACC1 localized in the chromatin-enriched fraction of the nucleus and interacted with Retinoid Acid Receptors (RARα) in the nucleus. TACC1 depletion in the cell led to decreased RARα and TRα ligand-dependent transcriptional activity and to delocalization of TR from the nucleus to the cytoplasm.

From these experimental studies we propose that TACC1 might be a scaffold protein building up a transcriptional complex around the NRs we studied. This function of TACC1 might account for its involvement in several forms of tumour development.

• Animals
• Histone Acetyltransferases/physiology
• Humans
• Neoplasms/metabolism
• Nuclear Receptor Coactivator 1
• Nuclear Receptor Coactivator 2/physiology
• Nuclear Receptor Coactivator 3
• Trans-Activators/physiology
• Transcription Factors/physiology
• Transcription, Genetic

• P01 DK059820-099003 NIDDK NIH HHS
• R01 CA112403-04S1 NCI NIH HHS
• R01 CA119689-05 NCI NIH HHS
• R01 CA112403-05 NCI NIH HHS
• R01 HD007857-40 NICHD NIH HHS
• R01 DK058242-05 NIDDK NIH HHS
• R01 DK058242-06A1 NIDDK NIH HHS
• R01DK058242 NIDDK NIH HHS
• R01 HD008188-39 NICHD NIH HHS
• R01CA119689 NCI NIH HHS
• R01 CA112403 NCI NIH HHS
• P01 DK059820 NIDDK NIH HHS
• R01CA112403 NCI NIH HHS
• R01 CA119689-04 NCI NIH HHS
• R01 CA112403-04 NCI NIH HHS
• R01 HD007857 NICHD NIH HHS
• R01HD07857 NICHD NIH HHS
• R01 DK058242-08 NIDDK NIH HHS
• P01 DK059820-089003 NIDDK NIH HHS
• R01 HD008188 NICHD NIH HHS
• R01HD08818 NICHD NIH HHS
• P01 DK059820-10 NIDDK NIH HHS
• P01DK059820 NIDDK NIH HHS
• R01 DK058242 NIDDK NIH HHS
• R01 CA119689 NCI NIH HHS