Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
Más filtros











Base de datos
Intervalo de año de publicación
1.
Leukemia ; 30(2): 417-22, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26490489

RESUMEN

Identification of patient sub-groups with smoldering multiple myeloma (SMM) at high risk of progression to active disease (MM) is an important goal. 18F-FDG PET/CT (positron emission tomography (PET) integrated with computed tomography (PET/CT) using glucose labelled with the positron-emitting radionuclide (18)F) allows for assessing early skeletal involvement. Identification of osteolytic lesions by this technique has recently been incorporated into the updated International Myeloma Working Group criteria for MM diagnosis. However, no data are available regarding the impact of focal lesions (FLs) without underlying osteolysis on time to progression (TTP) to MM. We hence prospectively studied a cohort of 120 SMM patients with PET/CT. PET/CT was positive in 16% of patients (1 FL: 8, 2 FLs: 3, >3 FLs: 6, diffuse bone marrow involvement: 2). With a median follow-up of 2.2 years, 38% of patients progressed to MM, in a median time of 4 years, including 21% with skeletal involvement. The risk of progression of those with positive PET/CT was 3.00 (95% confidence interval 1.58-5.69, P=0.001), with a median TTP of 1.1 versus 4.5 years for PET/CT-negative patients. The probability of progression within 2 years was 58% for positive versus 33% for negative patients. In conclusion, PET/CT positivity significantly increased the risk of progression of SMM to MM. PET/CT could become a new tool to define high-risk SMM.


Asunto(s)
Mieloma Múltiple/diagnóstico por imagen , Osteólisis/diagnóstico por imagen , Tomografía de Emisión de Positrones , Anciano , Progresión de la Enfermedad , Femenino , Fluorodesoxiglucosa F18 , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Imagen Multimodal , Estudios Prospectivos , Radiofármacos , Tomografía Computarizada por Rayos X
2.
Mol Cell Biol ; 20(22): 8623-33, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11046157

RESUMEN

The Hoxb1 autoregulatory element comprises three HOX-PBX binding sites. Despite the presence of HOXB1 and PBX1, this enhancer fails to activate reporter gene expression in retinoic acid-treated P19 cell monolayers. Activation requires cell aggregation in addition to RA. This suggests that HOX-PBX complexes may repress transcription under some conditions. Consistent with this, multimerized HOX-PBX binding sites repress reporter gene expression in HEK293 cells. We provide a mechanistic basis for repressor function by demonstrating that a corepressor complex, including histone deacetylases (HDACs) 1 and 3, mSIN3B, and N-CoR/SMRT, interacts with PBX1A. We map a site of interaction with HDAC1 to the PBX1 N terminus and show that the PBX partner is required for repression by the HOX-PBX complex. Treatment with the deacetylase inhibitor trichostatin A not only relieves repression but also converts the HOX-PBX complex to a net activator of transcription. We show that this activation function is mediated by the recruitment of the coactivator CREB-binding protein by the HOX partner. Interestingly, HOX-PBX complexes are switched from transcriptional repressors to activators in response to protein kinase A signaling or cell aggregation. Together, our results suggest a model whereby the HOX-PBX complex can act as a repressor or activator of transcription via association with corepressors and coactivators. The model implies that cell signaling is a direct determinant of HOX-PBX function in the patterning of the animal embryo.


Asunto(s)
Acetiltransferasas/metabolismo , Histona Desacetilasas/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Saccharomyces cerevisiae , Animales , Sitios de Unión , Proteína de Unión a CREB , Línea Celular , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Elementos de Facilitación Genéticos , Inhibidores Enzimáticos/farmacología , Histona Acetiltransferasas , Inhibidores de Histona Desacetilasas , Proteínas de Homeodominio/metabolismo , Humanos , Ácidos Hidroxámicos/farmacología , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética
3.
Mol Cell Biol ; 19(11): 7577-88, 1999 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-10523646

RESUMEN

HOX, PBX, and MEIS transcription factors bind DNA through a homeodomain. PBX proteins bind DNA cooperatively as heterodimers with MEIS family members and also with HOX proteins from paralog groups 1 to 10. MEIS proteins cooperatively bind DNA with ABD-B class HOX proteins of groups 9 and 10. Here, we examine aspects of dimeric and higher-order interactions between these three homeodomain classes. The most significant results can be summarized as follows. (i) Most of PBX N terminal to the homeodomain is required for efficient cooperative binding with HOXD4 and HOXD9. (ii) MEIS and PBX proteins form higher-order complexes on a heterodimeric binding site. (iii) Although MEIS does not cooperatively bind DNA with ANTP class HOX proteins, it does form a trimer as a non-DNA-binding partner with DNA-bound PBX-HOXD4. (iv) The N terminus of HOXD4 negatively regulates trimer formation. (v) MEIS forms a similar trimer with DNA-bound PBX-HOXD9. (vi) A related trimer (where MEIS is a non-DNA-binding partner) is formed on a transcriptional promoter within the cell. (vii) We observe an additional trimer class involving non-DNA-bound PBX and DNA-bound MEIS-HOXD9 or MEIS-HOXD10 heterodimers that is enhanced by mutation of the PBX homeodomain. (viii) In this latter trimer, PBX is likely to contact both MEIS and HOXD9/D10. (ix) The stability of DNA binding by all trimers is enhanced relative to the heterodimers. These findings suggest novel functions for PBX and MEIS in modulating the function of DNA-bound MEIS-HOX and PBX-HOX heterodimers, respectively.


Asunto(s)
Proteínas de Homeodominio/metabolismo , Proteínas Nucleares , Factores de Transcripción/metabolismo , Proteína con Homeodominio Antennapedia , Sitios de Unión , Proteínas de Unión al ADN/metabolismo , Dimerización , Proteínas de Homeodominio/clasificación , Sustancias Macromoleculares , Modelos Genéticos , Familia de Multigenes , Proteína 1 del Sitio de Integración Viral Ecotrópica Mieloide , Proteínas de Neoplasias/metabolismo , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Unión Proteica , Estructura Cuaternaria de Proteína , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/clasificación
4.
J Biol Chem ; 273(21): 13273-9, 1998 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-9582372

RESUMEN

HOX proteins are dependent upon cofactors of the PBX family for specificity of DNA binding. Two regions that have been implicated in HOX/PBX cooperative interactions are the YPWM motif, found N-terminal to the HOX homeodomain, and the GKFQ domain (also known as the Hox cooperativity motif) immediately C-terminal to the PBX homeodomain. Using derivatives of the E2A-PBX oncoprotein, we find that the GKFQ domain is not essential for cooperative interaction with HOXA1 but contributes to the stability of the complex. By contrast, the YPWM motif is strictly required for cooperative interactions in vitro and in vivo, even with mutants of E2A-PBX lacking the GKFQ domain. Using truncated PBX proteins, we show that the YPWM motif contacts the PBX homeodomain. The presence of the GKFQ domain increases monomer binding by the PBX homeodomain 5-fold, and the stability of the HOXA1.E2A-PBX complex 2-fold. These data suggest that the GKFQ domain acts mainly to increase DNA binding by PBX, rather than providing a primary contact site for the YPWM motif of HOXA1. We have identified 2 residues, Glu-301 and Tyr-305, required for GKFQ function and suggest that this is dependent on alpha-helical character.


Asunto(s)
Proteínas de Unión al ADN/metabolismo , ADN/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Sitios de Unión , Línea Celular , Secuencia Conservada , Cartilla de ADN , Proteínas de Unión al ADN/química , Proteínas de Unión al ADN/genética , Humanos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Conformación Proteica , Proteínas Proto-Oncogénicas/química , Proteínas Proto-Oncogénicas/genética
5.
Mol Cell Biol ; 15(8): 3989-97, 1995 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-7623795

RESUMEN

Homeoprotein products of the Hox/HOM gene family pattern the animal embryo through the transcriptional regulation of target genes. We have previously shown that the labial group protein HOXA-1 has intrinsically weak DNA-binding activity due to residues in the N-terminal arm of its homeodomain (M. L. Phelan, R. Sadoul, and M. S. Featherstone, Mol. Cell. Biol. 14:5066-5075, 1994). This observation, among others, suggests that HOX and HOM proteins require cofactors for stable interactions with DNA. We have demonstrated that a putative HOX cofactor, PBX1A, participates in cooperative DNA binding with HOXA-1 and the Deformed group protein HOXD-4. Three Abdominal-B class HOX proteins failed to cooperate with PBX1A. We mapped the interacting domain of HOXD-4 to the YPWMK pentapeptide motif, a conserved sequence found N terminal to the homeodomain of HOXA-1 and many other homeoproteins but absent from the Abdominal-B class. The naturally occurring fusion of the transcriptional activation domain of E2A with PBX1 creates an oncoprotein implicated in human pre-B-cell leukemias (M. P. Kamps, C. Murre, X.-H. Sun, and D. Baltimore, Cell 60:547-555, 1990; J. Nourse, J. D. Mellentin, N. Galili, J. Wilkinson, E. Starbridge, S. D. Smith, and M. L. Cleary, Cell 60:535-545, 1990). A pentapeptide mutation that abolished cooperative interaction with PBX1A in vitro also abrogated synergistic transcriptional activation with the E2A/PBX oncoprotein. The direct contact of PBX family members by the HOX pentapeptide is likely to play an important role in developmental and oncogenic processes.


Asunto(s)
Secuencia Conservada , Proteínas de Unión al ADN/metabolismo , ADN/metabolismo , Proteínas de Homeodominio/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Transcripción Genética , Secuencia de Aminoácidos , Secuencia de Bases , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Datos de Secuencia Molecular , Proteínas de Fusión Oncogénica/metabolismo , Factor de Transcripción 1 de la Leucemia de Células Pre-B , Unión Proteica , Conformación Proteica , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas
6.
Nucleic Acids Res ; 22(3): 376-82, 1994 Feb 11.
Artículo en Inglés | MEDLINE | ID: mdl-7907418

RESUMEN

The product of the murine Hoxd-4 (Hox-4.2) gene is a transcription factor that acts upon an autoregulatory element in Hoxd-4 upstream sequences (1). Using this activity as an assay in transient transfections of P19 embryonal carcinoma (EC) cells, we performed a mutational analysis to map functional domains in the HOXD-4 protein. The importance of the homeodomain was shown by a single amino acid change in this region that abolished activity. Deletion analysis revealed that many evolutionarily conserved regions outside of the homeodomain were dispensable for activation in our assay. Fusions to the GAL4 DNA-binding domain mapped a transcriptional activation function to the HOXD-4 proline-rich N-terminus. The proline-rich transcription factor AP2 squelched activation by HOXD-4 and by GAL4/HOXD-4 N-terminus fusion proteins. Together, these results suggest that HOXD-4 harbors a transcriptional activation domain of the proline-rich type.


Asunto(s)
Proteínas de Unión al ADN/química , Genes Homeobox , Factores de Transcripción/química , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , Ratones , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Prolina , Regiones Promotoras Genéticas , Proteínas Recombinantes de Fusión/química , Relación Estructura-Actividad , Factor de Transcripción AP-2 , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética , Activación Transcripcional
7.
J Cell Biol ; 103(6 Pt 2): 2673-82, 1986 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-2432072

RESUMEN

During the active phase of myelination in myelin-deficient mutant mice (mld), myelin basic protein (MBP) synthesis is defective and the myelin lamellae are uncompacted. In these mutants, we found a fast metabolism of the myelin-associated glycoprotein (MAG) and of sulfatides, and the presence of cholesterol esters and a degradation product of MAG, dMAG, indicating that mld myelin was unstable. The increased synthesis of MAG and Wolfgram protein, two proteins present in uncompacted myelin sheath and paranodal loops, was demonstrated by high levels of messengers. Simultaneously, we found an accumulation of inclusion bodies, vacuoles, and rough endoplasmic reticulum in mld oligodendrocytes. This material was heavily immunostained for MAG. Furthermore, the developmental change between the two molecular forms of MAG (p72MAG/p67MAG) was delayed in mld mice. In 85-d-old mld mice, the MBP content increased and myelin lamellae became better compacted. In these mutants, dMAG was absent and MAG mRNAs were found in normal amounts. Furthermore, the fine structure of mld oligodendrocytes was normal and the MAG immunostaining was similar to age-matched controls. These results support a functional role for MBP in maintaining the metabolic stability and the compact structure of myelin. Furthermore, in the absence of MBP and myelin compaction, the regulation of the synthesis of at least two membrane proteins related to myelin cannot proceed.


Asunto(s)
Ratones Mutantes Neurológicos/fisiología , Proteína Básica de Mielina/deficiencia , Vaina de Mielina/metabolismo , Neuroglía/metabolismo , Oligodendroglía/metabolismo , Factores de Edad , Animales , Ratones , Microscopía Electrónica , Peso Molecular , Proteína Básica de Mielina/genética , Proteínas de la Mielina/biosíntesis , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Glicoproteína Asociada a Mielina , Oligodendroglía/ultraestructura , Biosíntesis de Proteínas , ARN Mensajero/genética , Sulfoglicoesfingolípidos/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA