Suchergebnisse

22 páginas, 4 figuras ; Endogenous glucocorticoids (GCs) are steroid hormones that signal in virtually all cell types to modulate tissue homeostasis throughout life. Also, synthetic GC derivatives (pharmacological GCs) constitute the first-line treatment in many chronic inflammatory conditions with unquestionable therapeutic benefits despite the associated adverse effects. GC actions are principally mediated through the GC receptor (GR), a ligand-dependent transcription factor. Despite the ubiquitous expression of GR, imbalances in GC signalling affect tissues differently, and with variable degrees of severity through mechanisms that are not completely deciphered. Congenital or acquired GC hypersensitivity or resistance syndromes can impact responsiveness to endogenous or pharmacological GCs, causing disease or inadequate therapeutic outcomes, respectively. Acquired GC resistance is defined as loss of efficacy or desensitization over time, and arises as a consequence of chronic inflammation, affecting around 30% of GC-treated patients. It represents an important limitation in the management of chronic inflammatory diseases and cancer, and can be due to impairment of multiple mechanisms along the GC signalling pathway. Among them, activation of the mitogen-activated protein kinases (MAPKs) and/or alterations in expression of their regulators, the dual-specific phosphatases (DUSPs), have been identified as common mechanisms of GC resistance. While many of the anti-inflammatory actions of GCs rely on GR-mediated inhibition of MAPKs and/or induction of DUSPs, the GC anti-inflammatory capacity is decreased or lost in conditions of excessive MAPK activation, contributing to disease susceptibility in tissue- and disease- specific manners. Here, we discuss potential strategies to modulate GC responsiveness, with the dual goal of overcoming GC resistance and minimizing the onset and severity of unwanted adverse effects while maintaining therapeutic potential. ; This research was funded by grants to P.P. SAF2017-88046-R, PID2020-114652RB-I00, to E.E.-P. BFU-2017-86906-R, and to C.C. PID2020-119875RB-100 (from MICINN, Spanish Government); also, to E.E.-P. from G.E. Carretero Fund for Science ; Peer reviewed

Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apoptosis of many different cell types. Synthetic ligands for several NRs have been the focus of extensive drug discovery efforts for cancer intervention. This review summarizes the roles in tumour growth and metastasis of several relevant NR family members, namely androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoic acid receptors (RARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). These studies are key to develop improved therapeutic agents based on novel modes of action with reduced side effects and overcoming resistance. ; This work was supported by grants from the Spanish Ministry of Economy and Competitivity (MINECO) to AFV and CC (SAF201789510R) , to AA (SAF201783289R) , to MV (SAF201784934R) , to PP (SAF201788046R) , to EE (BFU201786906R) , and to the NuRCaMeIn network (SAF201790604REDT) ; grants from the Spanish Ministry of Science, Innovation and Universities (MCNU) and Fondo Europeo de Desarrollo Regional (FEDER) to MR (RTI2018-095928-B100) and AC (PID2019104284RBI00/AEI/10.13039/501100011033) ; a grant from Instituto de Salud Carlos IIIto AA (CIBERONC CB/16/00228) ; grants from the Autonomous Community of Madrid to AA (B2017/BMD-3724) and MR (MOIRB2017/BMD3684) ; grants from Fundacio La Marato de TV3 to CC (20160530) , AFV (201605-31) and MR (20160532) ; a grant from the Government of the Autonomous Community of Basque Country, Department of Industry, Tourism and Trade to MV (Elkartek, KK-2018/00054) ; and a grant from La Caixa to EEP (CaixaImpulseCI0018) . JFD received a fellowship from the Spanish Ministry of Science, ...

The androgen receptor is a transcription factor that plays a key role in the development of prostate cancer, and its interactions with general transcription regulators are therefore of potential therapeutic interest. The mechanistic basis of these interactions is poorly understood due to the intrinsically disordered nature of the transactivation domain of the androgen receptor and the generally transient nature of the protein-protein interactions that trigger transcription. Here, we identify a motif of the transactivation domain that contributes to transcriptional activity by recruiting the C-terminal domain of subunit 1 of the general transcription regulator TFIIF. These findings provide molecular insights into the regulation of androgen receptor function and suggest strategies for treating castration-resistant prostate cancer. ; This work was supported by IRB, ICREA (X.S.), Obra Social "la Caixa" (E.D.M., E.S., and X.S.), MINECO (BIO2012-31043 and BIO2015-70092-R to X.S., BIO2014-53095-P to G.D.F.), Marató de TV3 (102030 to X.S. and 102031 to E.E.-P), the COFUND program of the European Commission (C.D.S.), the European Research Council (CONCERT, contract number 648201 to X.S.), the Ramón y Cajal program of MICINN (RYC-2011-07873 to C.W.B.), the Serra Hunter Program (E.E.-P.), AGAUR (SGR-2014-56RR14 to E.E.-P), and FEDER (G.D.F.). I.H. was supported by funding from the Chief Scientist's Office of the Scottish Government (ETM-258, ETM-382). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from MINECO (Government of Spain).