scholarly journals How to overcome the ATRA resistance with the 9aaTAD activation domains in retinoic acid receptors

2018 ◽  
Author(s):  
Martin Piskacek ◽  
Marek Havelka ◽  
Andrea Knight
Keyword(s):  
Retinoic Acid ◽  
Hormone Receptors ◽  
Activation Function ◽  
Receptor Activation ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Loss Of Function ◽  
Activation Domains ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

AbstractIn higher metazoa, the nuclear hormone receptors activate transcription trough their specific adaptors, nuclear hormone receptor cofactors NCoA, which are surprisingly absent in lower metazoa. In this study, we demonstrated that the 9aaTAD from NHR-49 receptor activates transcription as a small peptide. We showed, that the 9aaTAD domains are conserved in the human nuclear hormone receptors including HNF4, RARa, VDR and PPARg. The small 9aaTAD peptides derived from these nuclear hormone receptors also effectively activated transcription and that in absence of the NCoA adaptors. We identified adjacent inhibitory domains in the human HNF4 and RARa, which hindered their activation function.In acute promyelocytic leukaemia (PML-RARa), the receptor mutations often caused all-trans retinoic acid (ATRA) resistance. The fact that almost the entire receptor is needed for ATRA mediated receptor activation, this activation pathway is highly susceptible for loss of function when mutated. Nevertheless in the most of the reported mutants, the activation domains 9aaTAD are still intact. The release of activation 9aaTAD from its dormancy by a new drug might be the sound strategy in combat the ATRA resistance in PML leukaemia.Graphical Abstract

scholarly journals Reduced Carotenoid and Retinoid Concentrations and Altered Lycopene Isomer Ratio in Plasma of Atopic Dermatitis Patients

2018 ◽  
Author(s):  
Renata Lucas ◽  
Johanna Mihaly ◽  
Gordon M. Lowe ◽  
Daniel L. Graham ◽  
Monika Szklenar ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Retinoic Acid ◽  
Plasma Levels ◽  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Human Organism ◽  
Isomer Ratio ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

In the human organism various carotenoids are present of which, some are retinoid precursors. The bioactive derivatives of these retinoids are the retinoic acids, which can potently activate nuclear hormone receptors like the retinoic acid receptor and the retinoid X receptor. In our study using an HPLC analytical approach we aimed to assess how plasma carotenoid and retinoid concentrations along with the ratio of their isomers are altered in atopic dermatitis (AD) patients (n=20) compared to healthy volunteers (HV, n=20). We found that plasma levels of the carotenoids lutein (HV 198 ± 68 ng/ml, AD 158 ± 57 ng/ml), zeaxanthin (HV 350 ± 142 ng/ml, AD 236 ± 85) as well as the retinoids retinol (HV 216 ± 89 ng/ml, AD 167 ± 76 ng/ml) and all-trans-retinoic acid (HV 1.1 ± 0.6 ng/ml, AD 0.7 ± 0.5 ng/ml) were significantly lower in AD-patients, while lycopene, α-carotene and β-carotene levels were comparable. In addition the ratios of 13-cis vs. all-trans lycopene as well as 13-cis vs. all-trans retinoic acid were increased in the plasma of AD-patients indicating an AD-specific 13C-isomerisation. A positive correlation with SCORRAD was calculated with 13-cis vs. all-trans lycopene ratio, while a negative correlation was observed with zeaxanthin plasma levels. Based on our results we conclude that in the plasma of AD-patients various carotenoids and retinoids are at lower levels, while the ratio of lycopene isomers was also altered. The higher rate of lycopene and retinoic acid isomerisation products might be a consequence of AD or might result in an altered activation of nuclear hormone receptor signaling pathways and thus maybe partly be responsible for the AD-phenotype and additionally may represent a good plasma marker for AD.

scholarly journals Reduced Carotenoid and Retinoid Concentrations and Altered Lycopene Isomer Ratio in Plasma of Atopic Dermatitis Patients

Nutrients ◽  
2018 ◽  
Vol 10 (10) ◽  
pp. 1390 ◽  
Author(s):  
Renata Lucas ◽  
Johanna Mihály ◽  
Gordon Lowe ◽  
Daniel Graham ◽  
Monika Szklenar ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Retinoic Acid ◽  
Healthy Volunteers ◽  
Plasma Levels ◽  
Hormone Receptors ◽  
Nuclear Hormone Receptor ◽  
Human Organism ◽  
Isomer Ratio ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Carotenoids and retinoids are known to alter the allergic response with important physiological roles in the skin and the immune system. In the human organism various carotenoids are present, some of which are retinoid precursors. The bioactive derivatives of these retinoids are the retinoic acids, which can potently activate nuclear hormone receptors such as the retinoic acid receptor and the retinoid X receptor. In this study, we aimed to assess how plasma carotenoid and retinoid concentrations along with the ratio of their isomers are altered in atopic dermatitis (AD) patients (n = 20) compared to healthy volunteers (HV, n = 20). The study indicated that plasma levels of the carotenoids lutein (HV 198 ± 14 ng/mL, AD 158 ± 12 ng/mL, p = 0.02; all values in mean ± SEM), zeaxanthin (HV 349 ± 30 ng/mL, AD 236 ± 18 ng/mL, p ≤ 0.01), as well as the retinoids retinol (HV 216 ± 20 ng/mL, AD 167 ± 17 ng/mL, p = 0.04) and all-trans-retinoic acid (HV 1.1 ± 0.1 ng/mL, AD 0.7 ± 0.1 ng/mL, p = 0.04) were significantly lower in the AD-patients, while lycopene isomers, α-carotene, and β-carotene levels were comparable to that determined in the healthy volunteers. In addition, the ratios of 13-cis- vs. all-trans-lycopene (HV 0.31 ± 0.01, AD 0.45 ± 0.07, p = 0.03) as well as 13-cis- vs. all-trans-retinoic acid (HV 1.4 ± 0.2, AD 2.6 ± 0.6, p = 0.03) were increased in the plasma of AD-patients indicating an AD-specific 13-cis-isomerisation. A positive correlation with SCORAD was calculated with 13-cis- vs. all-trans-lycopene ratio (r = 0.40, p = 0.01), while a negative correlation was observed with zeaxanthin plasma levels (r = −0.42, p = 0.01). Based on our results, we conclude that in the plasma of AD-patients various carotenoids and retinoids are present at lower concentrations, while the ratio of selected lycopene isomers also differed in the AD-patient group. An increase in plasma isomers of both lycopene and retinoic acid may cause an altered activation of nuclear hormone receptor signaling pathways and thus may be partly responsible for the AD-phenotype.

scholarly journals Determinants of CoRNR-Dependent Repression Complex Assembly on Nuclear Hormone Receptors

2001 ◽  
Vol 21 (5) ◽  
pp. 1747-1758 ◽  
Author(s):  
Xiao Hu ◽  
Yun Li ◽  
Mitchell A. Lazar
Keyword(s):  
Retinoic Acid ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Nuclear Hormone Receptors ◽  
Complex Assembly ◽  
Acid Receptor ◽  
Repression Complex ◽  
The Individual

ABSTRACT Ligand-dependent exchange of coactivators and corepressors is the fundamental regulator of nuclear hormone receptor (NHR) function. The interaction surfaces of coactivators and corepressors are similar but distinct enough to allow the ligand to function as a switch. Multiple NHRs share features that allow corepressor binding, and each of two distinct corepressors (N-CoR and SMRT) contains two similar CoRNR motifs that interact with NHRs. Here we report that the specificity of corepressor-NHR interaction is determined by the individual NHR interacting with specific CoRNR boxes within a preferred corepressor. First, receptors have distinct preferences for CoRNR1 versus CoRNR2. For example, the retinoic acid receptor binds CoRNR1, while RXR interacts almost exclusively with CoRNR2. Second, the NHR preference for N-CoR or SMRT is due to differences in CoRNR1 but not CoRNR2. Moreover, within a single corepressor, affinity for different NHRs is determined by distinct regions flanking CoRNR1. The highly specific determinants of NHR-corepressor interaction and preference suggest that repression is regulated by the permissibility of selected receptor-CoRNR-corepressor combinations. Interestingly, different NHR surfaces contribute to binding of CoRNR1 and CoRNR2, suggesting a model to explain corepressor binding to NHR heterodimers.

scholarly journals Identification and characterization of a functional retinoic acid/thyroid hormone-response element upstream of the human insulin gene enhancer

1995 ◽  
Vol 309 (3) ◽  
pp. 863-870 ◽  
Author(s):  
A R Clark ◽  
M E Wilson ◽  
N J M London ◽  
R F L James ◽  
K Docherty
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Retinoic Acid Receptor ◽  
Nuclear Hormone Receptor ◽  
Insulin Gene ◽  
Acid Receptor ◽  
Trans Retinoic Acid ◽  
Human Insulin Gene ◽  
All Trans Retinoic Acid

A deletion analysis of the human insulin gene extending to 2 kb upstream of the transcription start site provided evidence of regulatory sequences located upstream of the insulin-linked polymorphic region (ILPR). Within this ILPR-distal region is a sequence (Ink, for insulin kilobase upstream) which contains three potential nuclear hormone-receptor half-sites, closely matching the consensus sequence AGGTCA. These sequences are arranged as a palindromic element with zero spacing over-lapping a direct repeat with 2 bp spacing. The Ink sequence was used in electrophoretic mobility-shift assays within nuclear extracts from COS-7 cells overexpressing the vitamin D, thyroid hormone or retinoic acid receptors, or from an insulin-expressing hamster cell line, HIT-T15. These studies suggest that the insulin-expressing cell line contains thyroid hormone and retinoic acid receptors at least, and that these receptors are able to recognize the Ink sequence. Three copies of the Ink sequence were placed upstream of the thymidine kinase promoter and firefly luciferase reporter gene. In COS-7 cells expressing the appropriate nuclear hormone receptor, this construct was responsive to both thyroid hormone (18-fold) and all-trans-retinoic acid (31-fold). In HIT-T15 cells the same construct responded to all-trans-retinoic acid, but not to thyroid hormone. Within the context of a 2 kb insulin gene fragment, the Ink sequence was shown to be activated by retinoic acid and by the retinoic acid receptor, but acted as a negative element in the presence of both retinoic acid and the retinoic acid receptor. Mutagenesis studies demonstrated that the palindromic sequence was important for the retinoic acid response, and for binding of complexes containing retinoic acid receptor. In human islets of Langerhans, retinoic acid was shown to stimulate insulin mRNA levels. These results demonstrate that a functional nuclear hormone-receptor-response element is located upstream of the human ILPR. As retinoic acid and thyroid hormone are frequently involved in developmental regulatory processes, it is possible that this element may be important in the process of islet cell differentiation.

9-cis-retinoic acid, a potent inducer of digit pattern duplications in the chick wing bud

Development ◽  
1993 ◽  
Vol 118 (3) ◽  
pp. 957-965 ◽  
Author(s):  
C. Thaller ◽  
C. Hofmann ◽  
G. Eichele
Keyword(s):  
Retinoic Acid ◽  
Hormone Receptors ◽  
Quantitative Agreement ◽  
Trans Form ◽  
Potent Inducer ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Wing Bud ◽  
Cis Isomer

The effects of retinoids are mediated by two types of receptors, the retinoic acid receptors (RARs) and the retinoid-X-receptors (RXRs). The physiological ligand of the RARs is all-trans-retinoic acid whereas RXRs have high affinity for 9-cis-retinoic acid, a naturally occurring retinoid isomer. RXRs are broadly expressed in embryonic and adult tissues, and they are capable of forming homodimers as well as heterodimers with RARs and other nuclear hormone receptors. The role of 9-cis-retinoic acid in regulating the activity of RXR homodimers and RXR-containing heterodimers is poorly understood in vivo. To begin to explore the function of 9-cis-retinoic acid in morphogenesis, we have examined the activity of this isomer in the chick wing. Using reverse transcriptase polymerase chain reaction analyses, we show that RXR gamma is expressed in stage 20 wing buds. Similar to all-trans-retinoic acid, the 9-cis-isomer induces pattern duplications when locally applied to chick wing buds, but the 9-cis isomer is about 25 times more potent than the all-trans form. Furthermore, applied all-trans-retinoic acid is converted to the 9-cis isomer in the wing bud. The ratio of 9-cis to all-trans-retinoic acid established in the tissue is approximately 1:25. This quantitative agreement between the degree of conversion and the 25-fold higher efficacy of the 9-cis isomer, raises the possibility that, at least in part, the effects of all-trans-retinoic acid on the wing pattern result from a conversion to the 9-cis isomer.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Tip60 Is a Co-activator Specific for Class I Nuclear Hormone Receptors

2001 ◽  
Vol 276 (50) ◽  
pp. 46841-46848 ◽  
Author(s):  
Luke Gaughan ◽  
Mark E. Brady ◽  
Susan Cook ◽  
David E. Neal ◽  
Craig N. Robson
Keyword(s):  
Nuclear Receptor ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Steroid Hormone ◽  
Receptor Activation ◽  
Nuclear Hormone Receptor ◽  
Class I ◽  
Nuclear Hormone Receptors ◽  
Steroid Hormone Receptor ◽  
Independent Manner

The nuclear hormone receptor superfamily is composed of a group of hormone-dependent transcription factors that play prominent roles in homeostatic events in vertebrates. A prerequisite for steroid hormone receptor activity is the binding of co-activator molecules to the activation function-2 domain of the receptor. The LXXLL motif/nuclear receptor box, contained within a number of co-activator molecules, mediates the interaction with nuclear hormone receptors. Tip60 (Tat-interactive protein 60 kDa), previously shown to bind to and enhance androgen receptor (AR)-mediated transactivation, contains a single nuclear receptor box at its extreme C terminus. We demonstrate that unlike members of the p160 co-activator family that interact predominantly with the N terminus of the AR in an LXXLL motif-independent manner, the LXXLL motif of Tip60 is required and is sufficient for AR interaction. Furthermore, by using the mammalian two-hybrid system and transient transfection experiments, we show that Tip60 preferentially interacts with and up-regulates class I nuclear receptors, suggesting that Tip60 is a steroid hormone receptor-specific co-activator. We conclude that Tip60 may specifically regulate a subset of nuclear hormone receptors, giving an indication to how regulated nuclear receptor activation can be achieved.

Antiproliferative effect of all-trans-retinoic acid in cholangiocarcinoma

2017 ◽  
Author(s):  
A Prawan ◽  
S Butsri ◽  
V Kukongviriyapan ◽  
L Senggunprai ◽  
S Kongpetch
Keyword(s):  
Retinoic Acid ◽  
Antiproliferative Effect ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid
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