JunB y la proliferación celular: mecanismos de control y dianas transcripcionales

El factor de transcripción AP-1, formado por los miembros de la familia Jun, Fos y ATF, es un mediador de la expresión génica en respuesta a un amplio abanico de estímulos extracelulares. AP-1 está involucrado en el control de la proliferación, la transformación celular y la apoptosis. El factor de transcripción JunB, miembro de la familia Jun, se comporta como supresor tumoral u oncogén dependiendo del contexto celular. Su sobreexpresión se asocia a la patogénesis de algunos linfomas, como el linfoma anaplásico de células grandes (LACG) o ciertos linfomas de Hodgkin, aunque el papel de JunB en el desarrollo tumoral está poco estudiado. Los niveles de JunB aumentan durante la fase S del ciclo celular pero decrecen dramáticamente en G2 dependiendo de la vía ubicuitina - proteasoma. En la presente tesis se ha identificado que la degradación de JunB en G2 depende de la fosforilación por la quinasa GSK3β y de la E3 ubicuitina ligasa SCFFBXW7. Hemos observado que la acumulación de JunB en mitosis a consecuencia de defectos en su mecanismo de degradación causa la represión transcripcional de la helicasa DDX11. Las células con niveles reprimidos de DDX11 muestran problemas de cohesión en las cromátidas hermanas y, por tanto, defectos en la segregación de cromosomas. Este fenotipo lo observamos en linfoma anaplásico de células grandes donde JunB está sobreexpresado. Hemos comprobado que en este linfoma el mecanismo de degradación de JunB en G2/M está inhibido debido a una activación constitutiva de la cascada de señalización ALK/PI3K/AKT que conduce a la inactivación de GSK3β. Estos estudios indican que la degradación de JunB en G2 es esencial para mantener la fidelidad genética durante la mitosis y que la pérdida de regulación de este mecanismo puede promover el desarrollo tumoral. Con el propósito de identificar nuevas dianas transcripcionales de JunB a través de las cuales pudiera estar contribuyendo al desarrollo tumoral se han llevado a cabo experimentos de inmunoprecipitación de cromatina seguida de secuenciación masiva (ChIP-seq) y un análisis transcriptómico en células tumorales en las que la expresión de JunB fue silenciada. La consecuencia fenotípica del silenciamiento de JunB es una parada del ciclo celular con una disminución del número de células en fase S. Entre las dianas transcripcionales identificadas destacan la helicasa de ADN ERCC2, el cofactor transcripcional CITED2 y la proteína de unión a actina GAS2L1, cuyas variaciones de expresión a consecuencia del silenciamiento de JunB explican la parada del ciclo celular observada. Como la progresión por el ciclo celular es esencial para la proliferación celular, la regulación de estos genes mediada por JunB representa un nuevo mecanismo por el que JunB contribuye a la tumorigénesis

Linfadenopatía relacionada con enfermedad por IgG4

We present the case of a 49 year old man without previous diseases but toxic habits, who consulted to our Inter- nal Medicine Outpatient department due to the presence of mild fever and painfull axillar lymphadenopathies lasting for 7 months, with no other accompanying symptoms. Image tests (echography and body-scan) con- firmed the presence of multiple pathologic size axillary and inguinal lymphadenopathies, being transferred to surgery to proceed with lymphadenectomy. Anatomopathological lymphadenopathy study showed plasmatic cells with predominance of IgG4, with a IgG4/IgG ratio > 0.4. Analytic study was unremarkable, except for a mild IgG4 elevated value. Corticosteroid therapy is started, achieving complete resolution.Hombre de 49 años que acudió a consulta de Medicina Interna por febrícula y adenopatías axilares dolorosas de 7 meses de evolución sin otra sintomatología asociada. No antecedentes personales de interés ni hábitos tóxicos. Analíticamente sin datos patológicos. En distintas pruebas de imagen (ecografía, tomografía axial computarizada de tórax-abdomen-pélvis), se confirmó la presencia de múltiples adenopatías de tamaño no despreciable axilares e inguinales, por lo que se derivó a Cirugía para extirpación de las mismas. El resultado de la anatomía patológica indicó células plasmáticas de predominio IgG4, presentándose cociente IgG4/IgG > 0,4. El resultado analítico fue normal, a excepción de una elevación leve de IgG4. Se inició tratamiento corticoideo, desapareciendo las mismas

SARS-CoV-2-encoded small RNAs are able to repress the host expression of SERINC5 to facilitate viral replication

19 páginas, 9 figuras, 1 tablaSerine incorporator protein 5 (SERINC5) is a key innate immunity factor that operates in the cell to restrict the infectivity of certain viruses. Different viruses have developed strategies to antagonize SERINC5 function but, how SERINC5 is controlled during viral infection is poorly understood. Here, we report that SERINC5 levels are reduced in COVID-19 patients during the infection by SARS-CoV-2 and, since no viral protein capable of repressing the expression of SERINC5 has been identified, we hypothesized that SARS-CoV-2 non-coding small viral RNAs (svRNAs) could be responsible for this repression. Two newly identified svRNAs with predicted binding sites in the 3'-untranslated region (3'-UTR) of the SERINC5 gene were characterized and we found that the expression of both svRNAs during the infection was not dependent on the miRNA pathway proteins Dicer and Argonaute-2. By using svRNAs mimic oligonucleotides, we demonstrated that both viral svRNAs can bind the 3'UTR of SERINC5 mRNA, reducing SERINC5 expression in vitro. Moreover, we found that an anti-svRNA treatment to Vero E6 cells before SARS-CoV-2 infection recovered the levels of SERINC5 and reduced the levels of N and S viral proteins. Finally, we showed that SERINC5 positively controls the levels of Mitochondrial Antiviral Signalling (MAVS) protein in Vero E6. These results highlight the therapeutic potential of targeting svRNAs based on their action on key proteins of the innate immune response during SARS-CoV-2 viral infection.This work has been supported by grant CSIC-COV19-106 (202020 E164) from the Spanish National Research Council (CSIC) to FA and FI, and grant from RTI2018-101291-B-I00 to EE from the Spanish Ministry of Science and InnovationPeer reviewe

Sleep and breast and prostate cancer risk in the MCC-Spain study

Breast and prostate cancers have been associated with circadian disruption. Some previous studies examined associations of sleep duration and breast or prostate cancer risk though findings remain inconsistent. This study examines associations of a range of detailed sleep characteristics and breast and prostate cancer risk in a large-scale population-based case-control study, MCC-Spain. A total of 1738 incident breast cancer cases, 1112 prostate cancer cases and frequency matched controls (n = 1910, and 1493 respectively) were recruited. Detailed data on habitual sleep duration, quality, timing, and daytime napping ("siesta") were collected at recruitment. Additional data on sleep habits during both the previous year and at age 40 years were also subsequently captured. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) were estimated. There were no associations of habitual sleep duration (h), timing of sleep, or any or specific sleep problems, and either breast and prostate cancer risk. There was a significant positive association of ever taking habitual siestas at recruitment and breast cancer risk (OR = 1.22, 95% CI 1.06-1.42), which strengthened with increased frequency or duration. There were also significant positive associations observed for both breast and prostate cancer, among those reporting recent sleep problems, but not sleep problems at age 40 years, in a subsequent circadian questionnaire. Adverse associations with siesta and disturbed sleep during the previous year likely reflect symptoms of developing/diagnosed cancer and comorbidities. Overall, there was no clear association between various sleep characteristics and breast or prostate cancer risk observed.Funding: The study was partially funded by the ‘Accion Transversal del Cancer’, approved by the Spanish Ministry Council on 11 October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, PI11/02213; PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI14/01219, PI14/0613, PI15/00069, PI15/00914, PI15/01032, PI17CIII/00034, CIBERESP CB06/02/0073), the Fundación Marqués de Valdecilla (API 10/09), the Junta de Castilla y León (LE22A10- 2), the Consejería de Salud of the Junta de Andalucía (PI-0571-2009, PI-0306-2011, salud201200057018tra), the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10), the Recercaixa (2010ACUP 00310), the Regional Government of the Basque Country, the European Commission grants FOOD-CT-2006-036224-HIWATE, the Spanish Association Against Cancer (AECC) Scientifc Foundation, the Catalan Government DURSI grant 2014SGR647, 2017SGR723, 2017SGR1085 and 2014SGR850, the Fundación Caja de Ahorros de Asturias and by the University of Oviedo. MCT is funded by a Ramón y Cajal fellowship (RYC-2017-01892) from the Spanish Ministry of Science, Innovation and Universities and co-funded by the European Social Fund. ISGlobal acknowledges support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program

Occupational Heat Exposure and Breast Cancer Risk in the MCC-Spain Study

[EN] Background: Mechanisms linking occupational heat exposure with chronic diseases have been proposed. However, evidence on occupational heat exposure and cancer risk is limited. Methods: We evaluated occupational heat exposure and female breast cancer risk in a large Spanish case-control study. We enrolled 1,738 breast cancer cases and 1,910 frequency-matched population controls. A Spanish job-exposure matrix, MatEmEsp, was used to assign estimates of the proportion of workers exposed (P >= 25% for at least 1 year) and work time with heat stress (wet bulb globe temperature ISO 7243) for each occupation. We used three exposure indices: ever versus never exposed, lifetime cumulative exposure, and duration of exposure (years). We estimated ORs and 95% confidence intervals (CI), applying a lag period of 5 years and adjusting for potential confounders. Results: Ever occupational heat exposure was associated with a moderate but statistically significant higher risk of breast cancer (OR 1.22; 95% CI, 1.01-1.46), with significant trends across categories of lifetime cumulative exposure and duration (P-trend = 0.01 and 0.03, respectively). Stronger associations were found for hormone receptor-positive disease (OR ever exposure = 1.38; 95% Cl, 1.12-1.67). We found no confounding effects from multiple other common occupational exposures; however, results attenuated with adjustment for occupational detergent exposure. Conclusions: This study provides some evidence of an association between occupational heat exposure and female breast cancer risk.SIThis study was partially funded by the “Accion Transversal del Cancer,” approved by the Spanish Ministry Council on October 11, 2007; the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/1359, PI09/00773, PI09/01286, PI09/01903, PI09/02078, PI09/01662, PI11/01403, PI11/01889, and PI12/00265); the Fundación Marqués de Valdecilla (API 10/09); the Junta de Castilla y León (LE22A10-2); the Consejería de Salud of the Junta de Andalucía (2009-S0143); the Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10); the Recercaixa (2010ACUP 00310); the Regional Government of the Basque Country; the Consejería de Sanidad de la Región de Murcia; the European Commission grants FOOD-CT-2006–036224-HIWATE; the Spanish Association Against Cancer (AECC) Scientific Foundation; the Catalan Government DURSI grant 2014SGR647; the Secretariat for Universities and Research of the Ministry of Business and Knowledge of the Government of Catalonia (2017SGR1085); the Fundación Caja de Ahorros de Asturias; and the University of Oviedo. M.C. Turner is funded by a Ramón y Cajal fellowship (RYC-2017-01892) from the Spanish Ministry of Science, Innovation and Universities and co-funded by the European Social Fund. The authors acknowledge support from the Spanish Ministry of Science and Innovation through the “Centro de Excelencia Severo Ochoa 2019–2023” Program (CEX2018-000806-S) and support from the Generalitat de Catalunya through the CERCA Program. Statistical assistance provided by Ana Espinosa Morano was greatly appreciated

Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design

Introduction: We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. Methods: Between 2008-2013, 10,183 persons aged 20-85 years were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,115 cases of a new diagnosis of prostate cancer, 1,750 of breast cancer, 2,171 of colorectal cancer, 492 of gastro-oesophageal cancer, 554 cases of chronic lymphocytic leukaemia (CLL) and 4,101 population-based controls matched by frequency to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. Discussion: This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain.The study was partially funded by the “Accion Transversal del Cancer”, approved on the Spanish Ministry Council on the 11th October 2007, by the Instituto de Salud Carlos III-FEDER (PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150), by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL, by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571), by the Conselleria de Sanitat of the Generalitat Valenciana (AP 061/10), by the Recercaixa (2010ACUP 00310), by the Regional Government of the Basque Country by European Commission grants FOOD-CT- 2006-036224-HIWATE, by the Spanish Association Against Cancer (AECC) Scientific Foundation, by the The Catalan Government DURSI grant 2009SGR1489

COVID-19 Severity and Survival over Time in Patients with Hematologic Malignancies: A Population-Based Registry Study

Mortality rates for COVID-19 have declined over time in the general population, but data in patients with hematologic malignancies are contradictory. We identified independent prognostic factors for COVID-19 severity and survival in unvaccinated patients with hematologic malignancies, compared mortality rates over time and versus non-cancer inpatients, and investigated post COVID-19 condition. Data were analyzed from 1166 consecutive, eligible patients with hematologic malignancies from the population-based HEMATO-MADRID registry, Spain, with COVID-19 prior to vaccination roll-out, stratified into early (February–June 2020; n = 769 (66%)) and later (July 2020–February 2021; n = 397 (34%)) cohorts. Propensity-score matched non-cancer patients were identified from the SEMI-COVID registry. A lower proportion of patients were hospitalized in the later waves (54.2%) compared to the earlier (88.6%), OR 0.15, 95%CI 0.11–0.20. The proportion of hospitalized patients admitted to the ICU was higher in the later cohort (103/215, 47.9%) compared with the early cohort (170/681, 25.0%, 2.77; 2.01–3.82). The reduced 30-day mortality between early and later cohorts of non-cancer inpatients (29.6% vs. 12.6%, OR 0.34; 0.22–0.53) was not paralleled in inpatients with hematologic malignancies (32.3% vs. 34.8%, OR 1.12; 0.81–1.5). Among evaluable patients, 27.3% had post COVID-19 condition. These findings will help inform evidence-based preventive and therapeutic strategies for patients with hematologic malignancies and COVID-19 diagnosis.Depto. de MedicinaFac. de MedicinaTRUEFundación Madrileña de Hematología y HemoterapiaFundación Leucemia y LinfomaAsociación Madrileña de Hematología y Hemoterapiapu

Polyamines interfere with protein ubiquitylation and cause depletion of intracellular amino acids: a possible mechanism for cell growth inhibition

[EN] Spermidine is a polyamine present in eukaryotes with essential functions in protein synthesis. At high concentrations spermidine and norspermidine inhibit growth by unknown mechanisms. Transcriptomic analysis of the effect of norspermidine on the plant Arabidopsis thaliana indicates upregulation of the response to heat stress and denatured proteins. Accordingly, these polyamines inhibit protein ubiquitylation, both in vivo (in yeast, Arabidopsis, and human Hela cells) and in vitro (with recombinant ubiquitin ligase). This interferes with protein degradation by the proteasome, a situation known to deplete cells of amino acids. Norspermidine treatment of yeast cells induces amino acid depletion, and supplementation of media with amino acids counteracts growth inhibition and cellular amino acid depletion but not inhibition of protein polyubiquitylation.This work was supported by grant PROMETEO II 2014/041 from Generalitat Valenciana, Valencia, Spain.Sayas Montañana, EM.; Pérez-Benavente, B.; Manzano, C.; Farràs, R.; Alejandro Martinez, S.; Del Pozo, J.; Ferrando Monleón, AR.... (2019). Polyamines interfere with protein ubiquitylation and cause depletion of intracellular amino acids: a possible mechanism for cell growth inhibition. FEBS Letters. 593(2):209-218. https://doi.org/10.1002/1873-3468.13299S2092185932Yoda, H., Fujimura, K., Takahashi, H., Munemura, I., Uchimiya, H., & Sano, H. (2009). Polyamines as a common source of hydrogen peroxide in host- and nonhost hypersensitive response during pathogen infection. 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New roles for AP-1/JUNB in cell cycle control and tumorigenic cell invasion via regulation of cyclin E1 and TGF-β2

International audienceAbstract Background JUNB transcription factor contributes to the formation of the ubiquitous transcriptional complex AP-1 involved in the control of many physiological and disease-associated functions. The roles of JUNB in the control of cell division and tumorigenic processes are acknowledged but still unclear. Results Here, we report the results of combined transcriptomic, genomic, and functional studies showing that JUNB promotes cell cycle progression via induction of cyclin E1 and repression of transforming growth factor (TGF)-β2 genes. We also show that high levels of JUNB switch the response of TGF-β2 stimulation from an antiproliferative to a pro-invasive one, induce endogenous TGF-β2 production by promoting TGF-β2 mRNA translation, and enhance tumor growth and metastasis in mice. Moreover, tumor genomic data indicate that JUNB amplification associates with poor prognosis in breast and ovarian cancer patients. Conclusions Our results reveal novel functions for JUNB in cell proliferation and tumor aggressiveness through regulation of cyclin E1 and TGF-β2 expression, which might be exploited for cancer prognosis and therapy

R71. Fotografia publicitària

Publicitat i Relacions Públiques. R71. Fotografia publicitària. Curs acadèmic 2008/2009