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Novel insights into the cytoplasmic function of promyelocytic leukaemia (PML) and PML-retinoic acid receptor-αBellodi, Cristian January 2008 (has links)
The promyelocytic leukaemia protein (PML) is a tumour suppressor initially identified in acute promyelocytic leukaemia (APL). In APL, PML and the retinoic acid receptor alpha (RARalpha) genes are fused as a consequence of the translocation t(15;17). The product of the chimeric gene is the oncogenic PML-RARalpha protein. The PML gene encodes multiple nuclear and cytoplasmic isoforms. PML nuclear isoforms (nPML) are the main components of the PML nuclear bodies (PML-NBs), sub-nuclear structures involved in the modulation of essential cellular players including the tumour suppressor p53. Nuclear PML has been intensively studied, while, the role of cytoplasmic PML remains poorly understood. Increasing evidence indicates that PML could bear cytoplasmic functions in both physiological and pathological settings. This study aims to gain more insights into the function of PML and PML-RARalpha cytoplasmic pool of proteins. Recently, two missense mutations resulting in truncated PML cytoplasmic protein (Mut PML) have been identified in aggressive APL cases. We found that Mut PML alters the structure and the function of the PML-NB mainly through the cytoplasmic relocation of nPML. Remarkably, Mut PML inhibits p53 transcriptional, growth suppressive and apoptotic functions. In the cytoplasm, Mut PML interacts and stabilizes PML-RARalpha, thus potentiating its block of RA-induced transcription and differentiation. A mutant of PML-RARalpha (Delta2) accumulating in the cytoplasm is able to inhibit RA-dependent transcription and differentiation, suggesting that cytoplasmic localization of PML-RARalpha may contribute to transformation. Finally, we found that Delta2 expression blocks G-CSF-dependent myeloid differentiation and causes partial transformation of primary haematopoietic progenitor cells.
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The Effect of Retinoic Acid on Rai1 and Identification of Retinoic Acid Receptor Binding Site in Human Rai1Xue, Bingjie 08 January 2014 (has links)
Previous studies showed haploinsufficiency of RAI1 is the main cause of Smith-Magenis syndrome (SMS). SMS is a developmental neurobehavioral syndrome characterized by intellectual disability, congenital anomalies, obesity, neurobehavioral abnormalities, and disrupted circadian sleep-wake pattern. SMS is caused by deletion or mutation of chromosomal region 17p11.2 that includes RAI1. Studies in the Elsea lab have shown that RAI1 is a dosage-sensitive gene. Haploinsufficiency of RAI1 leads to dysregulation of CLOCK, NR1D2, POMC, and BDNF, which are responsible for circadian rhythm, metabolism, and cognitive development. Based on the data from Elsea’s recent study on zebrafish, rai1 gene expression in zebrafish is regulated by retinoic acid. Treatment with retinoic acid increases the expression of rai1. In this study, we focused on the effect of retinoic acid on human RAI1 expression. We found the expression of RAI1 was enhanced by the treatment with retinoic acid. The different concentrations of the retinoic acid affect the levels of increase in expression, but we found little evidence that RAI1 expression was affected by the length of treatment time. In this study, we were unable to find consistency in the pattern of changes in the expression level in respect to the different treatment concentrations. We identified nine strong retinoic acid response element (RARE) candidate sites upstream of the start codon in human RAI1. Since there are possible RARE sites present in the upstream sequence of RAI1, it is more likely that RAI1 is regulated by retinoic acid. However, further experimental evidence will be needed to confirm those sites selected in silico are able to bind RAR/RXR heterodimers, to prove the selected sites are real RARE sites and were not identified by chance.
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Epigenetic gene regulation in multiple myeloma and mood disordersKalushkova, Antonia January 2013 (has links)
Epigenetics continues to be redefined and new discoveries are likely to revolutionise the field still further. This thesis explores different aspects of how epigenetic regulation of gene expression contributes to human disease. Paper I explores the function of the IKKα kinase in regulating gene expression through the nuclear retinoic acid receptor (RAR). We define a set of genes requiring IKKα for their expression and found recruitment of IKKα to the RAR dependent on structural motifs in its protein sequence. This interplay between the NFκB pathway and nuclear receptor regulated transcription is important to consider when designing therapeutic strategies. Papers II and III focus on the plasma cell malignancy multiple myeloma (MM) and define a gene regulatory circuit defining an underexpressed gene profile in MM dependent on the Polycomb proteins. We provide proof-of-principle that the use of small chemical inhibitors may be operational in reactivating genes silenced by H3K27me3 and that this leads to decreased tumour load and increased survival in the 5T33 in vivo model of MM. We explored the genome-wide distribution of H3K27me3 and H3K4me3, and defined their association with gene expression in freshly-isolated malignant plasma cells from MM patients. Importantly, H3K27me3-marked genes in MM associated with more aggressive stages of the disease and less favourable survival. We present evidence that gene targeting by H3K27me3 is likely to not only involve a small population of tumour cells, but rather represent a common MM profile and further provide a rationale for evaluating epigenetic therapeutics in MM. Paper IV shows that pro-inflammatory gene expression in monocytes of psychiatric patients can be induced in vitro by sodium pump inhibitors, as the steroid hormone ouabain. We suggest that the ouabain-induced gene expression is regulated by an intricate network involving microRNAs, Polycomb and the H3K27me3 demethylase JMJD3. Our data indicates that epigenetic regulators play a role in transmitting cues between intrinsic and/extrinsic stimuli and gene expression in psychiatric illness. This thesis provides novel insights on how seemingly unrelated pathways may converge on transcriptional regulation and evidence that epigenetic modifiers contribute to the pathogenesis of human complex diseases such as multiple myeloma and mood disorders.
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The Effect of HACE1 on RAR Protein StabilityPayne, Erin J. January 2011 (has links)
All-trans retinoic acid (RA), as a ligand for retinoic acid receptors (RAR) and retinoid X receptors (RXR), modulates their transcriptional activity. The AF-1 and AF-2 domains mediate the transcriptional activity. The ligand dependent activation of the AF-2 domain by RA is well understood to involve chromosome decompaction in the presence of ligand with the aid of coactivators. The mechanism of the ligand independent action of the AF-1 domain is less clear. The AF-1 domain of RARs may be regulated by interacting proteins such as HACE1. In vitro and in vivo studies in our lab have shown that HACE1 interacts with RARα1, - β1, -β2, -β3, and -γ1 at the variable AF-1 domain. Transactivation studies have shown that HACE1 represses RA dependent transcriptional activity of RARγ1, but not RARβ3 and RARα1. Our original hypothesis proposed that HACE1 represses RAR transcriptional activity by inhibiting RA-dependent degradation of RARs. Current data confirms previous observations that the half life of RARβ3 is shortened in the presence of RA, compared to a vehicle control. Protein stability assays show that HACE1 does not have an effect on degradation of RARβ3 and RARγ1; however, it increases the ligand independent degradation of RARα1.This data suggests the A/B domain of RARγ1 recruits HACE1 for binding which results in transcriptional repression. Also, in a separate mechanism, the A/B domain of RARα1 binds to HACE1 which then accelerates its degradation in a ligand independent manner. The mechanisms behind these novel roles of HACE1 will need to be studied further and may help in understanding the method of AF-1 transcactivation function. / Microbiology and Immunology
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The Role of Acinus in Retinoic Acid Signaling PathwayWang, Fang January 2014 (has links)
Retinoic acid receptor (RAR), a member of the steroid/thyroid hormone nuclear receptor superfamily, functions as a RA-dependent transcription activator bound to the RA response element (RARE) within the promoter or enhancer region of target genes. The transcriptional activity of RAR is modulated by a large number of coregulators including coactivators and corepressors. Acinus is a nuclear protein with three isoforms (Acinus-L, Acinus-S and Acinus-S'). Acinus-S' interacts with the A/B domain of RAR and represses RAR-regulated genes expression. Acinus (without isoform definition) has been identified as a component of nuclear speckles, the spliceosome and the exon junction complex (EJC), suggesting its localization in nuclear speckles and involvement in RNA processing. Acinus-S has been shown to localize in nuclear speckles. However, it is unclear whether the other two isoforms also localize in nuclear speckles. In addition, the role of Acinus in regulating pre-mRNA splicing is unclear. The goal of these studies was to examine the nuclear localization of Acinus-L and Acinus-S' and to determine the role of Acinus isoforms in RAR-dependent splicing. The sub-nuclear localization of Acinus-L and Acinus-S' was determined using fluorescence microscopy. Acinus-S' colocalizes with SC35 in nuclear speckles while Acinus-L localizes diffusely throughout the nucleoplasm. RA treatment has little effect on the sub-nuclear localization of Acinus-L and Acinus-S'. The domains/regions necessary for the distinct sub-nuclear localization of Acinus-L and Acinus-S' were identified. The speckled sub-nuclear localization of Acinus-S' is dependent on its C-terminal RS- and RD/E-rich region but is independent of the phosphorylation status of Ser-453 and Ser-604 within this region. The unique N-terminal SAP-motif of Acinus-L is responsible for its diffuse localization in the nucleus. Moreover, the sub-nuclear localization of Acinus isoforms is affected by each other, which is determined by the combinatorial effect of the more potent SAP motif of Acinus-L and the C-terminal RS- and RD/E-rich region in all Acinus isoforms. The C-terminal RS- and RD/E-rich region of Acinus mediates the colocalization of Acinus isoforms as well as with its interacting protein RNPS1. The role of Acinus isoforms in regulating pre-mRNA splicing was explored using in vivo splicing assays. Both Acinus-L and Acinus-S', with the activity of Acinus-L higher than that of Acinus-S', increase the splicing of a RA-responsive minigene containing a weak 5' splice site but not a RA-responsive minigene containing a strong 5' splice site. RA treatment further enhances the splicing activity of Acinus in a dose- and time-dependent manner, suggesting a RA-dependent activity in addition to a RA-independent activity of Acinus. The RA-independent effect of Acinus on the splicing of pre-mRNAs containing the weak 5' splice site occurs to varying degrees using minigene constructs containing several different promoters while the RA-dependent splicing activity of Acinus is specific for transcripts derived from the minigene driven by the RARE-containing promoter. This suggests that the ligand-dependent splicing activity of Acinus is related to the RA-activated RAR bound to the RARE. The ligand-dependent splicing activity of Acinus was further shown to be promoter-specific, depending on the ligand-dependent transcription activator. The RRM domain was identified to be necessary for the RA-dependent splicing activity of Acinus. The RA-independent splicing activity of Acinus is repressed by RNPS1. Unexpectedly, the C-terminal RS- and RD/E rich region is dispensable for the splicing activity of Acinus in regulating the minigene containing a weak 5' splice site. Importantly, measurement of the splicing of endogenous human RARâ and Bcl-x in vivo demonstrates that Acinus stimulates the use of the weaker alternative 5' splice site of these two genes in a RA-dependent manner for RARâ and in a RA-independent manner for Bcl-x. Taken together, these studies demonstrate the distinct sub-nuclear localization of Acinus-L and Acinus-S', and identified the domains that are responsible for their sub-nuclear localization, which shed light on possible distinct functions between Acinus isoforms. In addition, both Acinus-L and Acinus-S' have been shown to be splicing cofactors (with the activity of Acinus-L higher than that of Acinus-S') that facilitate constitutive splicing of pre-mRNAs containing a weak 5' splice site and regulate alternative splicing in favor of the isoform generated from the weaker alternative 5' splice site. Both Acinus-L and Acinus-S' have a RA-dependent splicing activity specific for RA-responsive genes, which suggests that Acinus functions in RAR-dependent splicing. / Biochemistry
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Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytesStoney, P.N., Helfer, Gisela, Rodrigues, D., Morgan, P.J., McCaffery, P.J. 03 November 2015 (has links)
Yes / Thyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus.
Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have
been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored
the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a
gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The
resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo
exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to
an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the
actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice
culture method was developed in which the Raldh1-expressing tanycytes were maintained. These slice cultures confirmed that
TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression
of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has
been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems
has the capability to mediate some of the functions of TH in the hypothalamus.
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Functional and structural studies of proteins involved in the development and nerve signaling = FEZ1, SCOC and RARA = Estudos funcionais e estruturais de proteínas envolvidas no desenvolvimento e sinalização nervosa: FEZ1, SCOC e RARA / Estudos funcionais e estruturais de proteínas envolvidas no desenvolvimento e sinalização nervosa : FEZ1, SCOC e RARAFurlan, Ariane Silva, 1986- 05 October 2013 (has links)
Orientador: Jörg Kobarg / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-23T08:43:43Z (GMT). No. of bitstreams: 1
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Previous issue date: 2013 / Resumo: O resumo poderá ser visualizado no texto completo da tese digital quando liberada / Abstract: The abstract is available with the full electronic document when available / Mestrado / Bioquimica / Mestra em Biologia Funcional e Molecular
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Cell-specific Role of Retinoic Acid Receptor Alpha (RARα) in Lipid MetabolismCassim Bawa, Fathima Nafrisha 26 April 2022 (has links)
No description available.
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Regulatory mechanisms of c-Myc and their role in Acute Myeloid LeukemiaUribesalgo Micàs, Iris 24 November 2010 (has links)
The c-Myc transcription factor is a key player in cell homeostasis, being commonly
deregulated in human carcinogenesis. In this PhD thesis we have addressed the question
how regulatory mechanisms restrain the oncogenic activity of c-Myc and its impact on cell
differentiation. In the first half, we report that PML promotes destabilization of c-Myc protein
and re-activation of c-Myc-repressed target genes. The consequent re-expression of the cell
cycle inhibitor CDKN1A/p21 mediates differentiation of leukemic cells. In the second half of
the thesis we identified a novel mechanism of gene regulation by c-Myc, which is mediated
through its interaction with DNA-bound RARα. In undifferentiated cells, c-Myc/Max dimers
cooperate with RARα in the repression of genes required for differentiation. Upon
phosphorylation of c-Myc by the previously identified Pak2, the complex switches from a
repressive to an activating function by releasing Max and recruiting transcriptional coactivators.
These findings add a new and at least partially Max-independent mechanism for
transcriptional regulation by c-Myc and also discover an unexpected function of c-Myc in
inhibiting and promoting cellular differentiation.
Taken together, our results describe two new mechanisms that counteract the oncogenic
activity of c-Myc. Both PML and Pak2 can be considered as tumor suppressors since they
modulate c-Myc function in a way that ultimately promotes differentiation of leukemic cells.
This knowledge provides the basis for novel approaches to be exploited for the development
of c-Myc-targeted therapies. / El factor de transcripció c-Myc juga un paper clau en l’homeòstasi cel·lular, essent
freqüentment desregulat en la carcinogènesi humana. En aquesta tesi s’ha estudiat com
diferents mecanismes reguladors poden frenar l’activitat oncogènica de c-Myc i el
subsegüent impacte en la diferenciació cel·lular. A la primera meitat de la tesi, es demostra
que PML promou la desestabilització de la proteïna c-Myc i, en conseqüència, la reactivació
dels genes diana reprimits per c-Myc. Entre aquests gens diana es troba l’inhibidor del cicle
cel·lular CDKN1A/p21, la reexpressió del qual provoca la diferenciació de cèl·lules
leucèmiques induïda per PML. En la segona meitat, s’identifica un nou mecanisme de
regulació transcripcional per part de c-Myc a través de la interacció amb RARα, el qual està
unit a l’ADN. En cèl·lules indiferenciades, els dimers c-Myc/Max cooperen amb RARα en la
repressió de gens essencials per a la diferenciació. Un cop c-Myc és fosforil·lat per la kinasa
Pak2, el complex de c-Myc amb RARα esdevé activador mitjançant la pèrdua de Max i el
reclutament de coactivadors transcripcionals. Aquest descobriment suposa un nou
mecanisme mitjançant el qual c-Myc pot exercicir la regulació gènica almenys en part
independentment de Max, i també revela una funció desconeguda de c-Myc en la inhibició i
promoció de la diferenciació cel·lular.
En conjunt, aquests resultats descriuen dos nous mecanismes que contrarestren l’activitat
oncogènica de c-Myc. PML i Pak2 poden ser considerats supressors de tumors ja que
modulen la funció de c-Myc per a promoure la diferenciació de les cèl·lules leucèmiques.
Aquests descobriments poden utilitzar-se com a base pel desenvolupament de noves
teràpies anti-tumorals que tinguin com a diana la proteïna c-Myc.
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Nuclear receptors in the Pacific oyster, Crassostrea gigas, as screening tool for determining response to environmental contaminantsVogeler, Susanne January 2016 (has links)
Marine environments are under constant pressure from anthropogenic pollution. Chemical pollutants are introduced into the aquatic environment through waste disposal, sewage, land runoff and environmental exploitation (harbours, fisheries, tourism) leading to disastrous effects on the marine wildlife. Developmental malformations, reproduction failure including sex changes and high death rates are commonly observed in aquatic animal populations around the world. Unfortunately, the underlying molecular mechanisms of these pollution effects, in particular for marine invertebrate species, are often unknown. One proposed mechanism through which environmental pollution affects wildlife, is the disruption of nuclear receptors (NRs), ligand-binding transcription factors in animals. Environmental pollutants can directly interact with nuclear receptors, inducing incorrect signals for gene expression and subsequently disrupt developmental and physiological processes. Elucidation of the exact mechanism in invertebrates, however, is sparse due to limited understanding of invertebrate endocrinology and molecular regulatory mechanisms. Here, I have investigated the presence, expression and function of NRs in the Pacific oyster, Crassostrea gigas, and explored their interrelation with known environmental pollutants. Using a suite of molecular techniques and bioinformatics tools I demonstrate that the Pacific oyster possesses a large variety of NR homologs (43 NRs), which display individual expression profiles during embryo/larval development and supposedly fulfil distinct functions in developmental and physiological processes. Functional studies on a small subset of oyster NRs provided evidence for their ability to regulate gene expression, including interactions with DNA, other NRs or small molecules (ligand-binding). Oyster receptors also show a high likeliness to be disrupted by environmental pollutants. Computational docking showed that the retinoid X receptor ortholog, CgRXR, is able to bind and be activated by 9-cis retinoic acid and by the well-known environmental contaminant tributyltin. A potential interaction between tributyltin and the peroxisome proliferator-activated receptor ortholog CgPPAR has also been found. In addition, exposure of oyster embryos to retinoic acids and tributyltin resulted in shell deformations and developmental failure. In contrast, computer modelling of another putative target for pollutants, the retinoic acid receptor ortholog CgRAR, did not indicate interactions with common retinoic acids, supporting a recently developed theory of loss of retinoid binding in molluscan RARs. Sequence analyses revealed six residues in the receptor sequence, which prevent the successful interaction with retinoid ligands. In conclusion, this investigative work aids the understanding of fundamental processes in invertebrates, such as gene expression and endocrinology, as well as further understanding and prediction of effects of environmental pollutants on marine invertebrates.
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