scholarly journals Is PPARβ/δa Retinoid Receptor?

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-5 ◽  
Author(s):  
Daniel C. Berry ◽  
Noa Noy
Keyword(s):  
Retinoic Acid ◽  
Fatty Acid Binding Protein ◽  
Nuclear Translocation ◽  
Retinoic Acid Receptor ◽  
Binding Protein ◽  
Retinoid Receptor ◽  
Expression Ratio ◽  
Fatty Acid Binding ◽  
Bona Fide ◽  
Crabp Ii

The broad ligand-binding characteristic of PPARβ/δhas long hampered identification of physiologically-meaningful ligands for the receptor. The observations that the activity of PPARβ/δis supported by fatty acid binding protein 5 (FABP5), which directly delivers ligands from the cytosol to the receptor, suggest thatbona fidePPARβ/δligands both activate the receptor, and trigger the nuclear translocation of FABP5. Using these criteria, it was recently demonstrated that all-trans-retinoic acid (RA), the activator of the classical retinoic acid receptor RAR, also serves as a ligand for PPARβ/δ. Partitioning of RA between its two receptors was found to be regulated by FABP5, which delivers it to PPARβ/δ, and cellular RA binding protein II (CRABP-II), which targets it to RAR. Consequently, RA activates PPARβ/δin cells that display a high FABP5/CRABP-II expression ratio. It remains to be clarified whether compounds other than RA may also serve as endogenous activators for this highly promiscuous protein.

scholarly journals Fatty Acid Binding Protein FABP5: A Novel Therapeutic Target in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2553-2553
Author(s):  
Metis Hasipek ◽  
Yihong Guan ◽  
Dale Grabowski ◽  
Jaroslaw P. Maciejewski ◽  
Hetty E. Carraway ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Therapeutic Target ◽  
Target Genes ◽  
Binding Protein ◽  
Single Agent ◽  
Model Systems ◽  
Fatty Acid Binding ◽  
Genetic Ablation ◽  
Crabp Ii

Introduction: Retinoic acid (RA), the active metabolite of vitamin A, influences biological processes by activating the retinoic acid receptor (RAR). RARs are ligand-controlled transcription factors that function as heterodimer with retinoid X receptors (RXRs) and regulate expression of target genes affecting homeostasis of cellular differentiation and death. The success of RAR activation in the treatment of acute promyelocytic leukemia (APL), particularly by the use of all-trans retinoic acid (ATRA) has stimulated considerable interest in the development of small molecules that can modulate RAR and RXR in AML cells. RA can also activate the pro-survival peroxisome proliferator-activated receptor β/δ (PPARβ/δ) in a context dependent manner. In the aqueous intracellular milieu, RA is transported by the cellular retinoid-binding protein CRABP-II, or by the fatty-acid-binding protein FABP5, depending on the ratio of FABP5 to CRABP-II and cellular levels of RA. In cells, expressing high CRABP-II and low FABP5, RA activates the RAR, whereas in the presence of the reverse ratio, RA activates PPARβ/δ. These two different modes of RA delivery leads to opposite cellular outcomes. Cells harboring high level of CRABP-II, RA is delivered to RAR leading to differentiation and growth arrest. However, FABP5 high expressing cells, RA is delivered to PPARβ/δ resulting in survival and proliferation. Therefore, preventing FABP5 from such antagonism may be a novel therapeutic strategy for AML with high FABP5. Here, we report the development of a therapeutic approach using a specific FABP5 inhibitor (iFABP5) that facilitates the delivery of RA to tumor suppressor RAR. Methods: Genetic as well as pharmacologic models in AML cell lines were used to validate the therapeutic target by decoupling PPARβ/δ and RAR/RXR pathways. Knockdown and overexpression of key regulators of these pathways were rationally used to understand pro-survival effects of FABP5 overexpression. The efficacy of small molecule pharmacophore were evaluated in vitro in cell free and cell culture model systems as well as in vivo small animal model systems as a proof of therapeutic concept. Results: We analyzed AML samples from different cohorts (Beat AML and TCGA) for the expression levels of genes involved in RAR and PPARβ/δ pathways. Most of the AML patients have upregulation of pro-survival PPARβ/δ pathway genes including FABP5 and downregulation of differentiating promoting RAR pathway genes including critical RA chaperone CRABP2. On the otherhand, ATRA sensitive APL patients and cell lines have lower expression of FABP5 compared to AML. We established FABP5 as a therapeutic target for ATRA sensitization in AML cell line THP1. Genetic ablation of FABP5 using shRNA sensitizes THP1 cells to ATRA treatment compared to scramble control cells. We used in silico approach to develop a novel small molecule iFABP5 that binds to recombinant FABP5 (Kd= 2x10-7) with a 56-fold higher affinity compared to ATRA (Kd=11x10-6 Mole) in a cell free fluorescence reporter binding assay using 8-Anilino-1-naphthalenesulfonic acid (ANS). Efficacy of iFABP5 as a single agent and in combination with ATRA was evaluated in THP1, HL-60, K562, and OCI-AML5 cells. The effect of the combination was most pronounced in THP-1 cells. The iFABP5 synergizes with ATRA and induces the differentiation at 72 hours as assessed by both CD11b and CD14 levels. Treatment of cells with single agent iFABP5 leads to downregulation of PPARβ/δ target genes and upregulation of RAR target genes consistent with the genetic ablation of shFABP5. THP1 cells stably expressing shRNA targeting FABP5 has significant growth perturbation in a NSG mouse model compared to non-targeting shRNA. Pre-clinical in vivo evaluation of iFABP5 in combination with ATRA is ongoing as a therapeutic proof of concept. Conclusion: The lack of effective ATRA response in AML might be due to an aberrant activation of pro-survival PPARβ/δ pathway, which negatively affects ATRA-regulated gene expression and its antileukemic activity. Reprogramming of the RA delivery to RAR pathway with the addition of a small molecular inhibitor of FABP5 could potentially restore therapeutic effects of ATRA in FABP5 over expressing cases of AML subtypes. Disclosures Maciejewski: Novartis: Consultancy; Alexion: Consultancy.

scholarly journals Identification of a non-classical three-dimensional nuclear localization signal in the intestinal fatty acid binding protein

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0242312
Author(s):  
Mariana Suárez ◽  
Lucía Canclini ◽  
Adriana Esteves
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Fatty Acid Binding Protein ◽  
Nuclear Translocation ◽  
Binding Protein ◽  
Three Dimensional ◽  
Long Chain Fatty Acids ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
Localization Signal

The intestinal fatty acid binding protein (FABP) is a small protein expressed along the small intestine that bind long-chain fatty acids and other hydrophobic ligands. Several lines of evidence suggest that, once in the nucleus, it interacts with nuclear receptors, activating them and thus transferring the bound ligand into the nucleus. Previous work by our group suggests that FABP2 would participate in the cytoplasm-nucleus translocation of fatty acids. Because the consensus NLS is absent in the sequence of FABP2, we propose that a 3D signal could be responsible for its nuclear translocation. The results obtained by transfection assays of recombinant wild type and mutated forms of Danio rerio Fabp2 in Caco-2 cell cultures, showed that lysine 17, arginine 29 and lysine 30 residues, which are located in the helix-turn-helix region, would constitute a functional non-classical three-dimensional NLS.

scholarly journals Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Receptor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest

2002 ◽  
Vol 22 (8) ◽  
pp. 2632-2641 ◽  
Author(s):  
Anuradha S. Budhu ◽  
Noa Noy
Keyword(s):  
Retinoic Acid ◽  
Mammary Carcinoma ◽  
Transcriptional Activity ◽  
Retinoic Acid Receptor ◽  
Binding Protein ◽  
Carcinoma Cells ◽  
Acid Receptor ◽  
Acid Binding Protein ◽  
Mammary Carcinoma Cells ◽  
Crabp Ii

ABSTRACT Cellular retinoic acid-binding protein II (CRABP-II) is an intracellular lipid-binding protein that associates with retinoic acid with a subnanomolar affinity. We previously showed that CRABP-II enhances the transcriptional activity of the nuclear receptor with which it shares a common ligand, namely, the retinoic acid receptor (RAR), and we suggested that it may act by delivering retinoic acid to this receptor. Here, the mechanisms underlying the effects of CRABP-II on the transcriptional activity of RAR and the functional consequences of these effects were studied. We show that CRABP-II, a predominantly cytosolic protein, massively undergoes nuclear localization upon binding of retinoic acid; that it interacts with RAR in a ligand-dependent fashion; and that, in the presence of retinoic acid, the CRABP-II-RAR complex is a short-lived intermediate. The data establish that potentiation of the transcriptional activity of RAR stems directly from the ability of CRABP-II to channel retinoic acid to the receptor. We demonstrate further that overexpression of CRABP-II in MCF-7 mammary carcinoma cells dramatically enhances their sensitivity to retinoic acid-induced growth inhibition. Conversely, diminished expression of CRABP-II renders these cells retinoic acid resistant. Taken together, the data unequivocally establish the function of CRABP-II in modulating the RAR-mediated biological activities of retinoic acid.

Differential distribution patterns of CRABP I and CRABP II transcripts during mouse embryogenesis

Development ◽  
1992 ◽  
Vol 115 (4) ◽  
pp. 973-987 ◽  
Author(s):  
E. Ruberte ◽  
V. Friederich ◽  
G. Morriss-Kay ◽  
P. Chambon
Keyword(s):  
Retinoic Acid ◽  
Retinoic Acid Receptor ◽  
Binding Protein ◽  
Distribution Patterns ◽  
Retinol Binding Protein ◽  
Differential Distribution ◽  
Mouse Embryogenesis ◽  
Crabp I ◽  
Crabp Ii ◽  
Gut Endoderm

We have compared the transcript distribution of cellular retinoic acid binding protein (CRABP) I and II genes in mouse embryos at various stages of development. Both CRABP transcripts are present in embryonic structures from the earliest stages studied and exhibit specific patterns of distribution, suggesting that the two retinoic acid (RA) binding proteins perform different functions during mouse embryogenesis. The CRABP I transcript distribution correlates well with structures known to be targets of excess retinoid-induced teratogenesis (e.g. neural crest cells and hindbrain), suggesting that cells expressing CRABP I are those that cannot tolerate high levels of RA for their normal developmental function. The embryonic structures expressing CRABP II transcripts include those structures that have been shown to be adversely affected by excess of retinoids, such as limbs and hindbrain, but CRABP II transcripts are also found in structures not known to be specifically vulnerable to raised RA levels. The CRABP II gene is coexpressed with retinoic acid receptor (RAR)-beta and cellular retinol binding protein (CRBP) I genes in a number of tissues such as the gut endoderm, hypophysis and interdigital mesenchyme, all of which are devoid of CRABP I transcripts. Interestingly, the expression of the three genes, RAR-beta, CRABP II and CRBP I, is induced by retinoic acid, which suggests a link between the synthesis of RA from retinol and the control of expression of subsets of RA-responsive genes. The transcript distribution of CRABP I and II is discussed in relation to the teratogenic effects of RA, and compared to the RA-sensitive pattern of expression of other important developmental genes.

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