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Nat Commun ; 13(1): 3056, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35650206


Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.

Leucemia Linfocítica Crónica de Células B , Complejo Represivo Polycomb 1 , Leucemia-Linfoma Linfoblástico de Células Precursoras , Carcinogénesis , Núcleo Celular/metabolismo , Proteínas de Fusión bcr-abl/metabolismo , Humanos , Fosfoproteínas Fosfatasas/metabolismo , Complejo Represivo Polycomb 1/metabolismo , Proteínas Proto-Oncogénicas c-vav/genética , Proteínas Proto-Oncogénicas c-vav/metabolismo
Mucosal Immunol ; 8(4): 785-98, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25389033


Although interleukin (IL)-13 and neurotrophins are functionally important for the pathogenesis of immune responses, the interaction of these pathways has not been explored. Herein, by interrogating IL-13-induced responses in human epithelial cells we show that neurotrophic tyrosine kinase receptor, type 1 (NTRK1), a cognate, high-affinity receptor for nerve growth factor (NGF), is an early transcriptional IL-13 target. Induction of NTRK1 was accompanied by accumulation of activating epigenetic marks in the promoter; transcriptional and epigenetic changes were signal transducer and activator of transcription 6 dependent. Using eosinophilic esophagitis as a model for human allergic inflammation, we found that NTRK1 was increased in inflamed tissue and dynamically expressed as a function of disease activity and that the downstream mediator of NTRK1 signaling early growth response 1 protein was elevated in allergic inflammatory tissue compared with control tissue. Unlike NTRK1, its ligand NGF was constitutively expressed in control and disease states, indicating that IL-13-stimulated NTRK1 induction is a limiting factor in pathway activation. In epithelial cells, NGF and IL-13 synergistically induced several target genes, including chemokine (C-C motif) ligand 26 (eotaxin-3). In summary, we have demonstrated that IL-13 confers epithelial cell responsiveness to NGF by regulating NTRK1 levels by a transcriptional and epigenetic mechanism and that this process likely contributes to allergic inflammation.

Epigénesis Genética , Regulación de la Expresión Génica , Hipersensibilidad/genética , Hipersensibilidad/metabolismo , Interleucina-13/metabolismo , Receptor trkA/genética , Transcripción Genética , Análisis por Conglomerados , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Esofagitis Eosinofílica/genética , Esofagitis Eosinofílica/metabolismo , Esofagitis Eosinofílica/patología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Silenciador del Gen , Humanos , Interleucina-13/farmacología , Factor de Crecimiento Nervioso/farmacología , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo
Phys Rev Lett ; 109(10): 106603, 2012 Sep 07.
Artículo en Inglés | MEDLINE | ID: mdl-23005314


Electrical spin injection into semiconductors paves the way for exploring new phenomena in the area of spin physics and new generations of spintronic devices. However the exact role of interface states in the spin injection mechanism from a magnetic tunnel junction into a semiconductor is still under debate. In this Letter, we demonstrate a clear transition from spin accumulation into interface states to spin injection in the conduction band of n-Ge. We observe spin signal amplification at low temperature due to spin accumulation into interface states followed by a clear transition towards spin injection in the conduction band from 200 K up to room temperature. In this regime, the spin signal is reduced to a value compatible with the spin diffusion model. More interestingly, the observation in this regime of inverse spin Hall effect in germanium generated by spin pumping and the modulation of the spin signal by a gate voltage clearly demonstrate spin accumulation in the germanium conduction band.

Pneumologie ; 44 Suppl 1: 526-8, 1990 Feb.
Artículo en Alemán | MEDLINE | ID: mdl-1695001


Exogenous substance P is a powerful stimulant of tracheal gland secretion but the contribution of endogenous neuropeptides to neurogenic gland secretion is unknown. Using the Ussing chamber technique, we measured the secretion of radiolabeled macromolecules from submucosal glands in the ferret. Neurokinins caused gland secretion through a neurokinin-1 (NK-1) receptor. Gland secretion caused by electric field stimulation of postganglionic nerve endings was not inhibited by a substance P antagonist and was not augmented by agents known to prevent neurokinin degradation in the tissue. We conclude that the release of endogenous neurokinins plays no rôle in neurally evoked gland secretion. This is despite the fact that endogenous neurokinins have been shown to be involved in vagally induced airway smooth muscle contraction and increased capillary permeability in the same species.

Glándulas Exocrinas/inervación , Moco/metabolismo , Neuroquinina A/fisiología , Neuroquinina B/fisiología , Sustancia P/fisiología , Tráquea/inervación , Animales , Femenino , Hurones , Masculino , Receptores de Neuroquinina-2 , Receptores de Neurotransmisores/fisiología
Phys Rev B Condens Matter ; 32(8): 5492-5495, 1985 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-9937783
Phys Rev B Condens Matter ; 31(8): 5494-5496, 1985 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-9936525