The nuclear receptor field: a historical overview and future challenges

In this article we summarize the birth of the field of nuclear receptors, the discovery ofuntransformed and transformed isoforms of ligand-binding macromolecules, the discovery of thethree-domain structure of the receptors, and the properties of the Hsp90-based heterocomplexresponsible for the overall structure of the oligomeric receptor and many aspects of the biologicaleffects. The discovery and properties of the subfamily of receptors called orphan receptors is alsooutlined. Novel molecular aspects of the mechanism of action of nuclear receptors and challengesto resolve in the near future are discussed.Fil: Mazaira, Gisela Ileana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lotufo, Cecilia Maricel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Daneri Becerra, Cristina del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sivils, Jeffrey C.. University of Texas at El Paso; Estados UnidosFil: Soto, Olga B.. University of Texas at El Paso; Estados UnidosFil: Cox, Marc B.. University of Texas at El Paso; Estados UnidosFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin

The interplay between serine proteases and caspase-1 regulates the autophagy-mediated secretion of Interleukin-1 beta in human neutrophils

Neutrophils play major roles against bacteria and fungi infections not only due to their microbicide properties but also because they release mediators like Interleukin-1 beta (IL-1β) that contribute to orchestrate the inflammatory response. This cytokine is a leaderless protein synthesized in the cytoplasm as a precursor (pro-IL-1β) that is proteolytically processed to its active isoform and released from human neutrophils by secretory autophagy. In most myeloid cells, pro-IL-1β is processed by caspase-1 upon inflammasome activation. Here we employed neutrophils from both healthy donors and patients with a gain-of-function (GOF) NLRP3-mutation to dissect IL-1β processing in these cells. We found that although caspase-1 is required for IL-1β secretion, it undergoes rapid inactivation, and instead, neutrophil serine proteases play a key role in pro-IL-1β processing. Our findings bring to light distinctive features of the regulation of caspase-1 activity in human neutrophils and reveal new molecular mechanisms that control human neutrophil IL-1β secretion.Fil: Keitelman, Irene Angélica. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Shiromizu, Carolina Maiumi. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Danielián, Silvia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Jancic, Carolina Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Marti, Marcelo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Fuentes, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Yancoski, Judith. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Vera Aguilar, Douglas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Rosso, David Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Goris, Verónica. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Buda, Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Katsicas, María Martha. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Galigniana, Mario D.. Universidad de Buenos Aires; ArgentinaFil: Galletti, Jeremías Gastón. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Sabbione, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Trevani, Analía Silvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentin

Acción biológica de la inmunofilina de alto peso molecular FKBP51 en procesos malignos

Las inmunofilinas son proteínas con actividad enzimática de peptidilprolyl-isomerasa que unen drogas inmunosupresoras. La inmunofilina FKBP51 forma complejos con la chaperona HSP90 y une al macrólido FK506. En este trabajo, demostramos que FKBP51 es una fosfoproteína cuyo grado de fosforilación condiciona su localización subcelular, siendo ello regulado por balance hormonal. Una importante fracción subcelular de FKBP51 es mitocondrial, migra al núcleo por estrés, cumple funciones antiapoptóticas, y es sobreexpresada por células tumorales. La subunidad hTERT de telomerasa también es una proteína-cliente de HSP90 fuertemente inducida en células cancerosas. Demostramos que FKBP51 co-inmunoprecipita con complejos hTERT?HSP90. Tanto el inhibidor de HSP90 radicicol como la sobreexpresión del dominio TPR de FKBP51 (el interactuante con HSP90) favorecen la relocalización citoplásmica de hTERT. La actividad enzimática de telomerasa es significativamente mejorada por FKBP51. Tratamientos de células tumorales con FK506 muestran una disminución de la vibilidad celular, y tratamientos de ratones Scid/Nod portando tumores xenográficos con FK506 mostraron una significativa reducción del crecimiento tumoral. Como FK506 muestra afinidad por otras inmunofilinas, ensayamos a una nueva droga sintética que es selectiva para FKBP51, SAFit1, la que mostró resultados similares. Estos estudios demuestran que FKBP51 es un nuevo factor antiapoptótico relacionado con el desarrollo tumoral.Immunophilins are a family of proteins with peptidylprolyl-isomerase enzymatic activity. They also bind immunosuppressive drugs, a phenomenon that inhibits their isomerase activity. FKBP51 is an HSP90-binding cochaperone able to bind the immunosuppressant macrolide FK506. Nonetheless, FKBP51 is not related to immunosuppression, a mechanism that depends on the immunophilin FKBP12. FKP51 forms complexes with the molecular chaperone Hsp90 via TPR (tetratricopetide repeats) domains, and via TPR domains FKBP51 relates to HSP90-binding proteins such as sterid receptors, tyrosine-kinases and transcription factors. In this study, it is demonstrated for the first time that FKBP51 is a phosphoprotein whose phosphorylation status affects its subcellular localization. This is regulated by hormonal balance. An important fraction of FKBP51 is mitochondrial, which is unexpected since FKBP51 lacks of a known mitochondrial localization signal. Upon the onset of several situations of stress, FKBP51 translocates to the nucleus in an HSF1-dependent mechanism. Interestingly, FKBP51 shows antiapoptotic properties and is overexpressed in cancer cells, where it is constitutively located in the nuclei. The hTERT subunit of telomerase is also an HSP90 client‐protein highly expressed in cancer cells that favors their clonal expansion. In this work we demonstrate that FKBP51 co‐immunoprecipitates with hTERT•HSP90 complexes in an HSP90-dependent fashion. Thus, the HSP90 inhibitor radicicol or the overexpression of the immunophilin TPR domain (required for such association) relocalizes hTERT to the cytoplasm. Importantly, telomerase enzymatic activity is significantly enhanced by FKBP51, a process where the peptidyl-prolyl isomerase activity of the immunophilin is essential. In vitro treatment of tumor cells with FK506 decreases cell viability, whereas in vivo treatment of Scid/Nod mice carrying xenographic tumors, significantly decreases tumor growth. Inasmuch as FK506 could also be bound by other immunophilins, SAFit1, a new selective compound specifically designed for FKBP51 was assayed. Since the experimental results where similar to those shown by FK506, we conclude that they are mediated by FKBP51 and not by other immunophilin. The exposure of cells to oxidative stress leads to the activation of HSF1, which in turn favors the induction of hTERT expression as it is demonstrated by the lack of such induction of HSF1 KO cells. These studies demonstrate that FKBP51 is a novel antiapoptotic factor that migrates to the nucleus and enhances telomerase activity, which in turn favors tumor development.Fil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Htert expression is regulated by the activation of HSf1

Cancer cells achieve proliferative immortality by upregulating telomerase. hTERT is the catalytic subunit with reverse-transcriptase activity, which forms complexes with a template functional RNA, Hsp90, p23, and other accessory proteins. Recently, we demonstrated that two Hsp90-binding immunophilins, FKBP51 and FKBP52, are overexpressed in cancer cells and associated to hTERT.Fil: Lotufo, Cecilia Maricel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Mario Daniel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaLXIII Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica; LXVI Reunión Anual de la Sociedad Argentina de Inmunología y Reunión Anual de la Sociedad Argentina de FisiologíaMar del plataArgentinaSociedad Argentina de Investigación ClínicaSociedad Argentina de InmunologíaSociedad Argentina de FisiologíaAsociación Argentina de Nanomedicina

Hsp90-binding immunophilin FKBP51 forms complexes with hTERT enhancing telomerase activity

FK506-binding proteins are members of the immunophilin family of proteins. Those immunophilins associated to the 90-kDa-heat-shock protein, Hsp90, have been proposed as potential modulators of signalling cascade factors chaperoned by Hsp90. FKBP51 and FKBP52 are the best characterized Hsp90-bound immunophilins first described associated to steroid-receptors. The reverse transcriptase subunit of telomerase, hTERT, is also an Hsp90 client-protein and is highly expressed in cancer cells, where it is required to compensate the loss of telomeric DNA after each successive cell division. Because FKBP51 is also a highly expressed protein in cancer tissues, we analyzed its potential association with hTERT·Hsp90 complexes and its possible biological role. In this study it is demonstrated that both immunophilins, FKBP51 and FKBP52, co-immunoprecipitate with hTERT. The Hsp90 inhibitor radicicol disrupts the heterocomplex and favors the partial cytoplasmic relocalization of hTERT in similar manner as the overexpression of the TPR-domain peptide of the immunophilin. While confocal microscopy images show that FKBP51 is primarily localized in mitochondria and hTERT is totally nuclear, upon the onset of oxidative stress, FKBP51 (but not FKBP52) becomes mostly nuclear colocalizing with hTERT, and longer exposure times to peroxide favors hTERT export to mitochondria. Importantly, telomerase activity of hTERT is significantly enhanced by FKBP51. These observations support the emerging role assigned to FKBP51 as antiapoptotic factor in cancer development and progression, and describe for the first time the potential role of this immunophilin favoring the clonal expansion by enhancing telomerase activity.Fil: Lagadari, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gallo, Luciana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin

Mitochondrial–nuclear communication by FKBP51 shuttling

The HSP90-binding immunophilin FKBP51 is a soluble protein that shows high homology and structural similarity with FKBP52. Both immunophilins are functionally divergent and often show antagonistic actions. They were first described in steroid receptor complexes, their exchange in the complex being the earliest known event in steroid receptor activation upon ligand binding. In addition to steroid-related events, several pleiotropic actions of FKBP51 have emerged during the last years, ranging from cell differentiation and apoptosis to metabolic and psychiatric disorders. On the other hand, mitochondria play vital cellular roles in maintaining energy homeostasis, responding to stress conditions, and affecting cell cycle regulation, calcium signaling, redox homeostasis, and so forth. This is achieved by proteins that are encoded in both the nuclear genome and mitochondrial genes. This implies active nuclear-mitochondrial communication to maintain cell homeostasis. Such communication involves factors that regulate nuclear and mitochondrial gene expression affecting the synthesis and recruitment of mitochondrial and nonmitochondrial proteins, and/or changes in the functional state of the mitochondria itself, which enable mitochondria to recover from stress. FKBP51 has emerged as a serious candidate to participate in these regulatory roles since it has been unexpectedly found in mitochondria showing antiapoptotic effects. Such localization involves the tetratricopeptide repeats domains of the immunophilin and not its intrinsic enzymatic activity of peptidylprolyl-isomerase. Importantly, FKBP51 abandons the mitochondria and accumulates in the nucleus upon cell differentiation or during the onset of stress. Nuclear FKBP51 enhances the enzymatic activity of telomerase. The mitochondrial-nuclear trafficking is reversible, and certain situations such as viral infections promote the opposite trafficking, that is, FKBP51 abandons the nucleus and accumulates in mitochondria. In this article, we review the latest findings related to the mitochondrial-nuclear communication mediated by FKBP51 and speculate about the possible implications of this phenomenon.Fil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lagadari, Mariana. Universidad Nacional de Entre Ríos; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gallo, Luciana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Piwien Pilipuk, Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Role of the Hsp90-immunophilin heterocomplex in cancer disease

The identification of new factors that may function as cancer markers and becomeeventual pharmacologic targets is a challenge that may influence the management of tumor developmentand management. Recent discoveries connecting Hsp90-binding immunophilins with theregulation of signalling events that can modulate cancer progression transform this family of proteinsin potential unconventional factors that may impact on the screening and diagnosis of malignantdiseases. Immunophilins are molecular chaperones that group a family of intracellular receptorsfor immunosuppressive compounds. A subfamily of the immunophilin family is characterizedby showing structural tetratricopeptide repeats, protein domains that are able to interact with theC-terminal end of the molecular chaperone Hsp90, and via the proper Hsp90-immunophilin complex,the biological properties of a number of client-proteins involved in cancer biology are modulated.Recent discoveries have demonstrated that two of the most studied members of this Hsp90-binding subfamily of immunophilins, FKBP51 and FKBP52, participate in several cellular processessuch as apoptosis, carcinogenesis progression, and chemoresistance. While the expressionlevels of some members of the immunophilin family are affected in both cancer cell lines andhuman cancer tissues compared to normal samples, novel regulatory mechanisms have emergedduring the last few years for several client-factors of immunophilins that are major players in cancerdevelopment and progression, among them steroid receptors, the transctiption factor NF-κBand the catalytic subunit of telomerase, hTERT. In this review, recent findings related to the biologicalproperties of both iconic Hsp90-binding immunophilins, FKBP51 and FKBP52, are reviewedwithin the context of their interactions with those chaperoned client-factors. The potentialroles of both immunophilins as potential cancer biomarkers and non-conventional pharmacologictargets for cancer treatment are discussed.Keywords: Heat-shock proteins; immunophilins; cancer; peptidylprolyl isomerase;Fil: de Leo, Sonia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Mazaira, Gisela Ileana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Erlejman, Alejandra Giselle. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentin

Neuroregenerative and neuroprotective actions of immunophilin ligands in murine models

Immunophilins (IMMs) are a family of intracellular proteins that bind immunosuppressive drugs. They are referred to as FK506-binding proteins (FKBPs) when they bind FK506, and cyclophilins (CyPs) when they bind cyclosporine A (CsA). In previous studies performed in cell cultures, we demonstrated that FK506 shows neuroregenerative and neuroprotective actions via FKBPs, the expression balance between FKBP52 and FKBP51 playing a key role during those processes.Fil: Daneri Becerra, Cristina del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Patiño Gaillez, Michelle Geraldine Sissel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaReunión Conjunta de Sociedades de BiocienciasBuenos AiresArgentinaSociedad Argentina de Investigacion ClinicaSociedad Argentina de Investigación en Bioquímica y Biología MolecularSociedad Argentina de InmunologíaSociedad Argentina de AndrologíaSociedad Argentina de BiofísicaSociedad Argentina de BiologíaSociedad Argentina de Farmacología ExperimentalSociedad Argentina de HematologíaSociedad Argentina de Protozoologí

Gene expression regulation by heat-shock proteins: the cardinal roles of HSF1 and Hsp90

The ability to permit gene expression is managed by a set of relatively well known regulatory mechanisms. Nonetheless, such property can also be acquired during the life span as a consequence of environmental stimuli. Interestingly, some acquired information can be passed to the next generation of individuals without modifying gene information, but instead, the manner cells read and process such information. Molecular chaperones are classically related to the proper preservation of protein folding and anti-aggregation properties, but one of them, Hsp90, is a refined sensor of protein function facilitating the biological activity of properly folded client proteins that already have a preserved tertiary structure. Interestingly, Hsp90 can also function as a critical switch able to regulate biological responses due to its association to key client proteins such as histone deacetylases or DNA methylases. Thus, a growing amount of evidence has connected the action of Hsp90 to post-translational modifications of soluble nuclear factors, DNA, and histones, which epigenetically affects gene expression upon the onset of an unfriendly environment. Such response is commanded by the activation of the transcription factor HSF1. Even though a great number of stresses of diverse nature are known to trigger the stress response by activation of HSF1, it is still unanswered whether there are different types of molecular sensors for each type of stimulus. In this article, we will discuss various aspects of the regulatory action of HSF1 and Hsp90 on transcriptional regulation, and how this regulation may impact genetic assimilation mechanisms and the health of individuals.Fil: Mazaira, Gisela Ileana. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; ArgentinaFil: Daneri Becerra, Cristina del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lotufo, Cecilia Maricel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Mario Daniel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

Regulation of FKBP51 and FKBP52 functions by post-translational modifications

FKBP51 and FKBP52 are two iconic members of the family of peptidyl-prolyl-(cis/trans)-isomerases (EC: 5.2.1.8), which comprises proteins that catalyze the cis/trans isomerization of peptidyl-prolyl peptide bonds in unfolded and partially folded polypeptide chains and native state proteins. Originally, both proteins have been studied as molecular chaperones belonging to the steroid receptor heterocomplex, where they were first discovered. In addition to their expected role in receptor folding and chaperoning, FKBP51 and FKBP52 are also involved in many biological processes, such as signal transduction, transcriptional regulation, protein transport, cancer development, and cell differentiation, just to mention a few examples. Recent studies have revealed that both proteins are subject of post-translational modifications such as phosphorylation, SUMOlyation, and acetylation. In this work, we summarize recent advances in the study of these immunophilins portraying them as scaffolding proteins capable to organize protein heterocomplexes, describing some of their antagonistic properties in the physiology of the cell, and the putative regulation of their properties by those post-translational modifications.Fil: Daneri Becerra, Cristina del Rosario. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Zgajnar, Nadia Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lotufo, Cecilia Maricel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ramos Hryb, Ana Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Piwien Pilipuk, Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Galigniana, Mario Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentin