scholarly journals Nuclear receptors for retinoic acid and thyroid hormone regulate transcription of keratin genes.

1990 ◽  
Vol 1 (12) ◽  
pp. 965-973 ◽  
Author(s):  
M Tomic ◽  
C K Jiang ◽  
H S Epstein ◽  
I M Freedberg ◽  
H H Samuels ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Epithelial Cells ◽  
Nuclear Receptors ◽  
Dna Sequences ◽  
Primary Cultures ◽  
Direct Interaction ◽  
Gene Promoters ◽  
Intermediate Filament Proteins ◽  
Keratin Gene

In the epidermis, retinoids regulate the expression of keratins, the intermediate filament proteins of epithelial cells. We have cloned the 5' regulatory regions of four human epidermal keratin genes, K#5, K#6, K#10, and K#14, and engineered constructs in which these regions drive the expression of the CAT reporter gene. By co-transfecting the constructs into epithelial cells along with the vectors expressing nuclear receptors for retinoic acid (RA) and thyroid hormone, we have demonstrated that the receptors can suppress the promoters of keratin genes. The suppression is ligand dependent; it is evident both in established cell lines and in primary cultures of epithelial cells. The three RA receptors have similar effects on keratin gene transcription. Our data indicate that the nuclear receptors for RA and thyroid hormone regulate keratin synthesis by binding to negative recognition elements in the upstream DNA sequences of the keratin genes. RA thus has a twofold effect on epidermal keratin expression: qualitatively, it regulates the regulators that effect the switch from basal cell-specific keratins to differentiation-specific ones; and quantitatively, it determines the level of keratin synthesis within the cell by direct interaction of its receptors with the keratin gene promoters.

scholarly journals Thyroid Hormones and Gamma Interferon Specifically Increase K15 Keratin Gene Transcription

2004 ◽  
Vol 24 (8) ◽  
pp. 3168-3179 ◽  
Author(s):  
Nada Radoja ◽  
Olivera Stojadinovic ◽  
Ahmad Waseem ◽  
Marjana Tomic-Canic ◽  
Vladana Milisavljevic ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Glucocorticoid Receptors ◽  
Basal Layer ◽  
Gamma Interferon ◽  
Gene Promoters ◽  
Epidermolysis Bullosa Simplex ◽  
Keratin Gene ◽  
Ifn Γ ◽  
Stratified Epithelia

ABSTRACT Basal layers of stratified epithelia express keratins K5, K14, and K15, which assemble into intermediate filament networks. Mutations in K5 or K14 genes cause epidermolysis bullosa simplex (EBS), a disorder with blistering in the basal layer due to cell fragility. Nonkeratinizing stratified epithelia, e.g., in the esophagus, produce more keratin K15 than epidermis, which alleviates the esophageal symptoms in patients with K14 mutations. Hypothesizing that increasing the cellular content of K15 could compensate for the mutant K14 and thus ease skin blistering in K14 EBS patients, we cloned the promoter of the K15 gene and examined its transcriptional regulation. Using cotransfection, gel mobility shifts, and DNase I footprinting, we have identified the regulators of K15 promoter activity and their binding sites. We focused on those that can be manipulated with extracellular agents, transcription factors C/EBP, AP-1, and NF-κB, nuclear receptors for thyroid hormone, retinoic acid, and glucocorticoids, and the cytokine gamma interferon (IFN-γ). We found that C/EBP-β and AP-1 induced, while retinoic acid, glucocorticoid receptors, and NF-κB suppressed, the K15 promoter, along with other keratin gene promoters. However, the thyroid hormone and IFN-γ uniquely and potently activated the K15 promoter. Using these agents, we could boost the amounts of K15 in human epidermis. Our findings suggest that treatments based on thyroid hormone and IFN-γ could become effective agents in therapy for patients with EBS.

scholarly journals Thyroid Hormone Signaling in Embryonic Stem Cells: Crosstalk with the Retinoic Acid Pathway

2020 ◽  
Vol 21 (23) ◽  
pp. 8945
Author(s):  
Mercedes Fernández ◽  
Micaela Pannella ◽  
Vito Antonio Baldassarro ◽  
Alessandra Flagelli ◽  
Giuseppe Alastra ◽  
...  
Keyword(s):  
Stem Cells ◽  
Retinoic Acid ◽  
Embryonic Stem Cells ◽  
Thyroid Hormone ◽  
Nuclear Receptors ◽  
Embryonic Stem ◽  
Embryoid Bodies ◽  
Postnatal Life ◽  
Gene And Protein Expression

While the role of thyroid hormones (THs) during fetal and postnatal life is well-established, their role at preimplantation and during blastocyst development remains unclear. In this study, we used an embryonic stem cell line isolated from rat (RESC) to study the effects of THs and retinoic acid (RA) on early embryonic development during the pre-implantation stage. The results showed that THs play an important role in the differentiation/maturation processes of cells obtained from embryoid bodies (EB), with thyroid hormone nuclear receptors (TR) (TRα and TRβ), metabolic enzymes (deiodinases 1, 2, 3) and membrane transporters (Monocarboxylate transporters -MCT- 8 and 10) being expressed throughout in vitro differentiation until the Embryoid body (EB) stage. Moreover, thyroid hormone receptor antagonist TR (1-850) impaired RA-induced neuroectodermal lineage specification. This effect was significantly higher when cells were treated with retinoic acid (RA) to induce neuroectodermal lineage, studied through the gene and protein expression of nestin, an undifferentiated progenitor marker from the neuroectoderm lineage, as established by nestin mRNA and protein regulation. These results demonstrate the contribution of the two nuclear receptors, TR and RA, to the process of neuroectoderm maturation of the in vitro model embryonic stem cells obtained from rat.

scholarly journals A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily.

1994 ◽  
Vol 14 (10) ◽  
pp. 7025-7035 ◽  
Author(s):  
R Apfel ◽  
D Benbrook ◽  
E Lernhardt ◽  
M A Ortiz ◽  
G Salbert ◽  
...  
Keyword(s):  
Amino Acid ◽  
Thyroid Hormone ◽  
Dna Binding ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Dna Sequences ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Retinoid Receptor

The steroid/hormone nuclear receptor superfamily comprises several subfamilies of receptors that interact with overlapping DNA sequences and/or related ligands. The thyroid/retinoid hormone receptor subfamily has recently attracted much interest because of the complex network of its receptor interactions. The retinoid X receptors (RXRs), for instance, play a very central role in this subfamily, forming heterodimers with several receptors. Here we describe a novel member of this subfamily that interacts with RXR. Using a v-erbA probe, we obtained a cDNA which encodes a novel 445-amino-acid protein, RLD-1, that contains the characteristic domains of nuclear receptors. Northern (RNA) blot analysis showed that in mature rats, the receptor is highly expressed in spleen, pituitary, lung, liver, and fat. In addition, weaker expression is observed in several other tissues. Amino acid sequence alignment and DNA-binding data revealed that the DNA-binding domain of the new receptor is related to that of the thyroid/retinoid subgroup of nuclear receptors. RLD-1 preferentially binds as a heterodimer with RXR to a direct repeat of the half-site sequence 5'-G/AGGTCA-3', separated by four nucleotides (DR-4). Surprisingly, this binding is dependent to a high degree on the nature of the spacing nucleotides. None of the known nuclear receptor ligands activated RLD-1. In contrast, a DR-4-dependent constitutive transcriptional activation of a chloramphenicol acetyltransferase reporter gene by the RLD-1/RXR alpha heterodimer was observed. Our data suggest a highly specific role for this novel receptor within the network of gene regulation by the thyroid/retinoid receptor subfamily.

Identification of the Retinoic Acid and Thyroid Hormone Receptor-Responsive Element in the Human K14 Keratin Gene

1992 ◽  
Vol 99 (6) ◽  
pp. 842-847 ◽  
Author(s):  
Marjana Tomic-Canic ◽  
Ivana. Sunjevaric ◽  
Irwin M Freedberg ◽  
Miroslav Blumenberg
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Keratin Gene ◽  
Responsive Element

COUP orphan receptors are negative regulators of retinoic acid response pathways

1992 ◽  
Vol 12 (10) ◽  
pp. 4666-4676
Author(s):  
P Tran ◽  
X K Zhang ◽  
G Salbert ◽  
T Hermann ◽  
J M Lehmann ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Nuclear Receptors ◽  
Thyroid Hormone Receptor ◽  
Cdna Probe ◽  
Specific Response ◽  
Retinoid Receptor ◽  
Orphan Receptors ◽  
Response Element ◽  
Response Elements

The vitamin hormone retinoic acid (RA) regulates many complex biological programs. The hormonal signals are mediated at the level of transcription by multiple nuclear receptors. These receptors belong to the steroid/thyroid hormone receptor superfamily that also includes a large number of orphan receptors whose biological roles have not yet been determined. Although much has been learned in recent years about RA receptor (RAR) functions, little is known about how specific RA response programs are restricted to certain tissues and cell types during development and in the adult. It has been recently shown that RAR activities are regulated by retinoid X receptors (RXR) through heterodimer formation. In an effort to isolate and further characterize nuclear receptors that modulate RAR and/or RXR activities, we have screened cDNA libraries by using a RXR alpha cDNA probe. Two clones, COUP alpha and COUP beta, identical and closely related to the orphan receptor COUP-TF, were obtained. We show that COUP proteins dramatically inhibit retinoid receptor activities on certain response elements that are activated by RAR/RXR heterodimers or RXR homodimers. COUP alpha and -beta bind strongly to these response elements, including a palindromic thyroid hormone response element and a direct repeat RA response element as well as an RXR-specific response element. In addition, we found that the previously identified COUP-TF binding site in the ovalbumin gene functions in vitro as an RA response element that is repressed in the presence of COUP. Our data suggest that the COUP receptors are a novel class of RAR and RXR regulators that can restrict RA signaling to certain elements. The COUP orphan receptors may thus play an important role in cell- or tissue-specific repression of subsets of RA-sensitive programs during development and in the adult.

Application of Machine Learning Methods in Predicting Nuclear Receptors and their Families

2020 ◽  
Vol 16 (5) ◽  
pp. 594-604 ◽  
Author(s):  
Zi-Mei Zhang ◽  
Zheng-Xing Guan ◽  
Fang Wang ◽  
Dan Zhang ◽  
Hui Ding
Keyword(s):  
Machine Learning ◽  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Germ Cell ◽  
Nuclear Receptors ◽  
Nuclear Factor ◽  
Fushi Tarazu ◽  
Learning Methods ◽  
Machine Learning Methods ◽  
Germ Cell Nuclear Factor

Nuclear receptors (NRs) are a superfamily of ligand-dependent transcription factors that are closely related to cell development, differentiation, reproduction, homeostasis, and metabolism. According to the alignments of the conserved domains, NRs are classified and assigned the following seven subfamilies or eight subfamilies: (1) NR1: thyroid hormone like (thyroid hormone, retinoic acid, RAR-related orphan receptor, peroxisome proliferator activated, vitamin D3- like), (2) NR2: HNF4-like (hepatocyte nuclear factor 4, retinoic acid X, tailless-like, COUP-TFlike, USP), (3) NR3: estrogen-like (estrogen, estrogen-related, glucocorticoid-like), (4) NR4: nerve growth factor IB-like (NGFI-B-like), (5) NR5: fushi tarazu-F1 like (fushi tarazu-F1 like), (6) NR6: germ cell nuclear factor like (germ cell nuclear factor), and (7) NR0: knirps like (knirps, knirpsrelated, embryonic gonad protein, ODR7, trithorax) and DAX like (DAX, SHP), or dividing NR0 into (7) NR7: knirps like and (8) NR8: DAX like. Different NRs families have different structural features and functions. Since the function of a NR is closely correlated with which subfamily it belongs to, it is highly desirable to identify NRs and their subfamilies rapidly and effectively. The knowledge acquired is essential for a proper understanding of normal and abnormal cellular mechanisms. With the advent of the post-genomics era, huge amounts of sequence-known proteins have increased explosively. Conventional methods for accurately classifying the family of NRs are experimental means with high cost and low efficiency. Therefore, it has created a greater need for bioinformatics tools to effectively recognize NRs and their subfamilies for the purpose of understanding their biological function. In this review, we summarized the application of machine learning methods in the prediction of NRs from different aspects. We hope that this review will provide a reference for further research on the classification of NRs and their families.

LEDGF regulation of alcohol and aldehyde dehydrogenases in lens epithelial cells: stimulation of retinoic acid production and protection from ethanol toxicity

2004 ◽  
Vol 287 (2) ◽  
pp. C508-C516 ◽  
Author(s):  
Nigar Fatma ◽  
Eri Kubo ◽  
Leo T. Chylack ◽  
Toshimichi Shinohara ◽  
Yoshio Akagi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Epithelial Cells ◽  
Specific Binding ◽  
Normal Growth ◽  
Cell Types ◽  
Lens Epithelial Cells ◽  
Ethanol Stress ◽  
Gene Promoters ◽  
Cellular Protection ◽  
Cellular Detoxification

Retinoic acid (RA) is required for the normal growth and maintenance of many cell types, including lens epithelial cells (LECs). Alcohol (ADH) and aldehyde (ALDH) dehydrogenases are implicated in cellular detoxification and conversion of vitamin A to RA. Lens epithelium-derived growth factor (LEDGF) provides cellular protection against stress by transactivating stress-associated genes. Here we show evidence that LEDGF binds and transactivates heat shock (nGAAn) and stress response (A/TGGGGA/T) elements in the promoters of ADH1, ADH4, and retinaldehyde 2 (RALDH2) genes. Electrophoretic mobility and supershift assays disclosed specific binding of LEDGF to nGAAn and A/TGGGGA/T elements in these gene promoters. Transfection experiments in LECs with promoters linked to a chloramphenicol acetyltransferase (CAT) reporter gene along with LEDGF cDNA revealed higher CAT activity. RT-PCR results confirmed that LECs overexpressing LEDGF contained increased levels of ADH1, ADH4, and RALDH2 mRNA. Notably, LECs displayed higher LEDGF mRNA and protein expression during ethanol stress. Cells overexpressing LEDGF typically exhibited elevated RA levels and survived well during ethanol stress. The present findings indicate that LEDGF is one of the transcriptional activators of these genes that facilitates cellular protection against ethanol stress and plays a role in RA production.

scholarly journals Specific Organization of the Negative Response Elements for Retinoic Acid and Thyroid Hormone Receptors in Keratin Gene Family

1997 ◽  
Vol 109 (4) ◽  
pp. 566-572 ◽  
Author(s):  
Nadezda Radoja ◽  
Danilo V. Diaz ◽  
Todd J. Minars ◽  
Irwin M. Freedberg ◽  
Miroslav Blumenberg ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Gene Family ◽  
Hormone Receptors ◽  
Negative Response ◽  
Thyroid Hormone Receptors ◽  
Keratin Gene ◽  
Response Elements
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