HIPK2 in the physiology of nervous system and its implications in neurological disorders.

HIPK2 is an evolutionary conserved serine/threonine kinase with multifunctional roles in stress response, embryonic development and pathological conditions, such as cancer and fibrosis. The heterogeneity of its interactors and targets makes HIPK2 activity strongly dependent on the cellular context, and allows it to modulate multiple signaling pathways, ultimately regulating cell fate and proliferation. HIPK2 is highly expressed in the central and peripheral nervous systems, and its genetic ablation causes neurological defects in mice. Moreover, HIPK2 is involved in processes, such as endoplasmic reticulum stress response and protein aggregate accumulation, and pathways, including TGF-ß and BMP signaling, that are crucial in the pathogenesis of neurological disorders. Here, we review the data about the role of HIPK2 in neuronal development, survival, and homeostasis, highlighting the implications in the pathogenesis of neurological disorders, and pointing out HIPK2 potentiality as therapeutic target and diagnostic or prognostic marker.

Localization of neuroglobin in the brain of R6/2 mouse model of Huntington's disease.

Neuroglobin (Ngb) is expressed in the central and peripheral nervous system, cerebrospinal fluid, retina, and endocrine tissues where it is involved in binding O2 and other gasotransmitters. Several studies have highlighted its endogenous neuroprotective function. Huntington's disease (HD), a dominant hereditary disease, is characterized by the gradual loss of neurons in discrete areas of the central nervous system. We analyzed the expression of Ngb in the brain tissue of a mouse model of HD, in order to define the role of Ngb with respect to individual cell type vulnerability in HD and to gender and age of mice. Our results showed different expressions of Ngb among neurons of a specific region and between different brain regions. We evidenced a decreased intensity of Ngb at 13 weeks of age, compared to 7 weeks of age. The double immunofluorescence and fluorescence resonance energy transfer (FRET) experiments showed that the co-localization between Ngb and huntingtin at the subcellular level was not close enough to account for a direct interaction. We also observed a different expression of Ngb in the striatum, depending on the sex and age of animals. These findings provide the first experimental evidence for an adaptive response of Ngb in HD, suggesting that Ngb may exert neuroprotective effects in HD beyond its role in reducing sensitivity to oxidative stress.

Lysine-specific demethylase LSD1 regulates autophagy in neuroblastoma through SESN2-dependent pathway.

Autophagy is a physiological process, important for recycling of macromolecules and maintenance of cellular homeostasis. Defective autophagy is associated with tumorigenesis and has a causative role in chemotherapy resistance in leukemia and in solid cancers. Here, we report that autophagy is regulated by the lysine-specific demethylase LSD1/KDM1A, an epigenetic marker whose overexpression is a feature of malignant neoplasia with an instrumental role in cancer development. In the present study, we determine that two different LSD1 inhibitors (TCP and SP2509) as well as selective ablation of LSD1 expression promote autophagy in neuroblastoma cells. At a mechanistic level, we show that LSD1 binds to the promoter region of Sestrin2 (SESN2), a critical regulator of mTORC1 activity. Pharmacological inhibition of LSD1 triggers SESN2 expression that hampers mTORC1 activity, leading to enhanced autophagy. SESN2 overexpression suffices to promote autophagy in neuroblastoma cells, while loss of SESN2 expression reduces autophagy induced by LSD1 inhibition. Our findings elucidate a mechanism whereby LSD1 controls autophagy in neuroblastoma cells through SESN2 transcription regulation, and we suggest that pharmacological targeting of LSD1 may have effective therapeutic relevance in the control of autophagy in neuroblastoma.

Translational control in the stress adaptive response of cancer cells: a novel role for the heat shock protein TRAP1.

TNF receptor-associated protein 1 (TRAP1), the main mitochondrial member of the heat shock protein (HSP) 90 family, is induced in most tumor types and is involved in the regulation of proteostasis in the mitochondria of tumor cells through the control of folding and stability of selective proteins, such as Cyclophilin D and Sorcin. Notably, we have recently demonstrated that TRAP1 also interacts with the regulatory protein particle TBP7 in the endoplasmic reticulum (ER), where it is involved in a further extra-mitochondrial quality control of nuclear-encoded mitochondrial proteins through the regulation of their ubiquitination/degradation. Here we show that TRAP1 is involved in the translational control of cancer cells through an attenuation of global protein synthesis, as evidenced by an inverse correlation between TRAP1 expression and ubiquitination/degradation of nascent stress-protective client proteins. This study demonstrates for the first time that TRAP1 is associated with ribosomes and with several translation factors in colon carcinoma cells and, remarkably, is found co-upregulated with some components of the translational apparatus (eIF4A, eIF4E, eEF1A and eEF1G) in human colorectal cancers, with potential new opportunities for therapeutic intervention in humans. Moreover, TRAP1 regulates the rate of protein synthesis through the eIF2α pathway either under basal conditions or under stress, favoring the activation of GCN2 and PERK kinases, with consequent phosphorylation of eIF2α and attenuation of cap-dependent translation. This enhances the synthesis of selective stress-responsive proteins, such as the transcription factor ATF4 and its downstream effectors BiP/Grp78, and the cystine antiporter system xCT, thereby providing protection against ER stress, oxidative damage and nutrient deprivation. Accordingly, TRAP1 silencing sensitizes cells to apoptosis induced by novel antitumoral drugs that inhibit cap-dependent translation, such as ribavirin or 4EGI-1, and reduces the ability of cells to migrate through the pores of transwell filters. These new findings target the TRAP1 network in the development of novel anti-cancer strategies.

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins.

Tumor necrosis factor receptor-associated protein-1 (TRAP1) is a mitochondrial (MITO) antiapoptotic heat-shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass-spectrometric analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 colocalize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopic analyses, and interact directly, as confirmed by fluorescence resonance energy transfer analysis. This is the first demonstration of TRAP1's presence in this cellular compartment. TRAP1 silencing by short-hairpin RNAs, in cells exposed to thapsigargin-induced ER stress, correlates with upregulation of BiP/Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, expression of specific MITO proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, as it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of the ER-mitochondria crosstalk.

Comportamiento clínico epidemiológico de los pacientes con psoriasis atendidos en el centro nacional de dermatología "Dr. Francisco José Gómez Urcuyo" en el péríodo comprendido de abril 2004 a abril 2005 / The patients' epidemic clinical behavior with psoriasis assisted in the national center of dermatology Dr. Francisco José Gómez Urcuyo in the understood péríodo of April 2004 to April 2005

La psoriasis es una dermatosis crónica, recidivantes, que se caracteriza por la presencia de placas eritomnatosas y escamosas que ocasionan alteraciones en la calidad de vida del paciente. No existen datos epidemiológicos nacionales respecto a la psoriasis en Nicaragua. Se hizo un estudio descriptivo de corte transversal acerca del comportamiento clínicoepidemiológico de la psoriasis en el Centro Nacional de Dermatología "Dr. Francisco José Gómes Urcuyo" en el período comprendido de abril del 2004 a abril 2005 con un universo de 284 pacientes diagnósticados con psoriasis que asistieron a consulta externa y al programa de psicodermatosis y para la recolección de la información se elaboró una encuesta con preguntas cerradas y se revisaron expedientes clínicos del departamento de estadística del Hospital donde se lleno la ficha de recolección de la información. De los 284 pacientes estudiados, 162 pertenecian al sexo femenino y 122 al sexo masculino. El grupo etáreo más afectado fue el de 51 años a más. Los principales factores desencadenantes fueron el estrés, alcoholismo, fenómeno isomórfico y las infecciones en menor frecuencia, el 50 porciento de los pacientes encuestados (46) tuvieron antecedentes familiares. El 56.34 por ciento iniciaron su cuadro con psoriasis antes de los 40 años. El índice de severidad y área de psoriasis (PASI) fue de leve a moderado. La topografia más frecuente fue la forma diseminada y predominó la psoriasis en placa. Debemos continuar realizando determinaciones para tener nuestros propios marcadores para conocer el comportamiento real de la psoriasis en Nicaragua. Los resultados se encasillan dentro de los rangos de la epidemiología mundial...

Caveolin transfection results in caveolae formation but not apical sorting of glycosylphosphatidylinositol (GPI)-anchored proteins in epithelial cells.

Most epithelial cells sort glycosylphosphatidylinositol (GPI)-anchored proteins to the apical surface. The "raft" hypothesis, based on data mainly obtained in the prototype cell line MDCK, postulates that apical sorting depends on the incorporation of apical proteins into cholesterol/glycosphingolipid (GSL) rafts, rich in the cholesterol binding protein caveolin/VIP21, in the Golgi apparatus. Fischer rat thyroid (FRT) cells constitute an ideal model to test this hypothesis, since they missort both endogenous and transfected GPI-anchored proteins to the basolateral plasma membrane and fail to incorporate them into cholesterol/glycosphingolipid clusters. Because FRT cells lack caveolin, a major component of the caveolar coat that has been proposed to have a role in apical sorting of GPI-anchored proteins (Zurzolo, C., W. Van't Hoff, G. van Meer, and E. Rodriguez-Boulan. 1994. EMBO [Eur. Mol. Biol. Organ.] J. 13:42-53.), we carried out experiments to determine whether the lack of caveolin accounted for the sorting/clustering defect of GPI-anchored proteins. We report here that FRT cells lack morphological caveolae, but, upon stable transfection of the caveolin1 gene (cav1), form typical flask-shaped caveolae. However, cav1 expression did not redistribute GPI-anchored proteins to the apical surface, nor promote their inclusion into cholesterol/GSL rafts. Our results demonstrate that the absence of caveolin1 and morphologically identifiable caveolae cannot explain the inability of FRT cells to sort GPI-anchored proteins to the apical domain. Thus, FRT cells may lack additional factors required for apical sorting or for the clustering with GSLs of GPI-anchored proteins, or express factors that inhibit these events. Alternatively, cav1 and caveolae may not be directly involved in these processes.

Estudo das cordas tendineas das valvulas comissurais da valva mitral. / A study of the chordae tendineae of the comissural valvules of the mitral valve

Os autores realizam um estudo anatomico de cordas tendineas das valvulas comissurais ou suplementares da valva mitral. Foram motivados a esta pesquisa pelas citacoes da literatura abordando patologias da valva mitral associados a comprometimento nas cordas tendineas de suas valvulas e a presenca de pequenas valvulas comissurais.No mateiral estudado, constando de 32 valvulas, procurou-se principalmente verificar o numero, distribuicao e localizacao das cordas tendineas. Os resultados obtidos demonstraram nao existir diferenca de numero e de localizacao dessas cordas tendineas nas valvulas comissurais em relacao as demais valvulas, a tal ponto que pudessem justificar possibilidade de patologias estarem associadas a um deficiente posicionamento dessas cordas tendineas