Implication of the tetraspanin CD9 in the immune system and cancer

Las tetraspaninas son moléculas de la superficie celular de ampliadistribución en los organismos eucarióticos. Poseen como característicaestructural peculiar cuatro dominios transmembranales, regionesN- y C-terminales intracitoplásmicas, y dos lazos extracelularesde distinto tamaño. También poseen un motivo de secuencia CCGen el lazo extracelular mayor, así como residuos polares conservadosen los dominios transmembranales. Las células sanguíneas delos mamíferos expresan combinaciones peculiares de distintas tetraspaninas,incluyendo los antígenos de diferenciación CD9, CD37,CD53, CD81/TAPA-1, CD82, CD151/PETA-3 y CD231/TALLA1.En este trabajo se resumen la estructura y las interacciones desus regiones citoplásmicas con proteínas del citoesqueleto y señalizadoras,como la proteína cinasa C (PKC) o la Fosfatidil-Inositol 4-cinasa (PI4-K). Sus interacciones específicas con otras tetraspaninas,con integrinas, antígenos de histocompatibilidad, y miembros dela superfamilia de las inmunoglobulinas son también revisadas.Las tetraspaninas son proteínas “adaptadoras” o “facilitadoras”.Al formar parte de complejos moleculares, modulan funcionescelulares clave que incluyen la fusión celular, la adhesión, lamigración, la diferenciación y la transducción de señales. Las tetraspaninasse organizan en una red con distintos niveles de asociación,determinados por su resistencia a la solubilización por detergentes.En concreto, se analizan las tetraspaninas como reguladorasdel Sistema Inmunitario gracias a sus interacciones con los receptoresde antígeno de los linfocitos T y B, las moléculas de histocompatibilidadde clase I y clase II, y los co-receptores CD2, CD4,CD5, CD8 y CD19. Por último, se revisa detalladamente el papelde la tetraspanina CD9 en la función de las células linfoides y mieloides,su relevancia en infecciones como el HIV, y la importanciade su asociación con integrinas en la progresión cancerosa

Tetraspanins are cell surface proteins widely distributed ineukaryotic organisms. They characteristically span four times theplasma membrane, have intracellular N and C terminal regions,and two extracellular loops of unequal size. Tetraspanins also possessa CCG motif in the large extracellular loop, and conservedpolar residues in the transmembrane domains. Mammalian bloodcells express different sets of tetraspanins including the differentiationantigens CD9, CD37, CD53, CD81/TAPA-1, CD82,CD151/PETA-3 and CD231/TALLA1.Here, tetraspanin structure and their cytoplasmic tail interactionswith cytoskeletal and signalling proteins like Protein kinaseC (PKC) or Phosphatidyl Inositol 4-kinase (PI4-K) are brieflysummarized. The specific interactions with other cell surface proteins,forming complexes with other tetraspanins and membersof the integrin family, MHC histocompatibility antigens, or membersof the immunoglobulin superfamily are also reviewed.Tetraspanins are considered as “adapter” or “facilitating” proteinsand, through their participation in complexes, they modulatekey cellular functions like cell fusion, adhesion, migration,differentiation and signal transduction. The organization of thetetraspanin web, based on different association levels determinedby their resistance to detergent solubilization, is described. In particular,tetraspanins participating in the regulation of the ImmuneSystem through interactions with the B- and T-cell receptors,the class I and class II MHC antigens, and co-receptors such asCD2, CD4, CD5, CD8, or CD19 are analyzed. At last, the role ofCD9 in myeloid and lymphoid cell function, its relevance to HIVinfection, and the importance of tetraspanin association with integrinsto cancer progression are described in detail

Modulación negativa del TCR por un mecanismo de todo-o-nada / All-or-none downregulation of the T cell antigen receptor

El contacto del TCR con MHC/antígeno resulta en su modulación y desaparición de la superficie celular. Recientemente hemos descrito que este proceso ocurre por al menos dos mecanismos: uno es dependiente de transmisión de señales, predomina a bajas concentraciones de antígeno y resulta en la modulación en trans de moléculas de TCR no contactadas. El otro requiere contacto directo y es independiente de transmisión de señales. En este artículo describimos que el TCR es modulado en una forma discontinua, es decir las células estimuladas oscilan de un estado no-modulado a otro completamente modulado sin transición aparente por estados intermedios, cuando las células T son estimuladas con altas dosis de antígeno o de anticuerpos anti-TCR. El fenómeno se reproduce cuando un receptor quimérico, que contiene la parte extracelular y transmembránica de CD8 y el tallo citoplásmico de CD3 , es entre cruzado con anticuerpos inmovilizados a un substrato. Este proceso de modulación de "todo-o-nada" no requiere de transmisión de señales o de polimerización del citoesqueleto de actina. El análisis por microscopía confocal muestra que el anticuerpo estimulante es tomado del substrato y concentrado junto con la quimera en un polo de la célula donde se constituye un sitio de nucleación para la formación de vesículas endocíticas. El efecto de "todo-o-nada" puede explicarse por la concentración lenta del TCR o de la quimera, seguido de la internalización rápida de los receptores agregados (AU)

The downregulation of the pro-apoptotic protein Par-4 is critical for Ras-induced survival and tumor progression.

Inhibition of apoptosis is an important characteristic of oncogenic transformation. The Par-4 gene product has recently been shown to be upregulated in cells undergoing apoptotic cell death, and its ectopic expression was shown to be critical in apoptosis. We demonstrate that expression of oncogenic Ras promotes a potent reduction of Par-4 protein and mRNA levels through a MEK-dependent pathway. In addition, the expression of permanently active mutants of MEK, Raf-1 or zetaprotein kinase C but not of phosphatidylinositol 3-kinase (PI 3-kinase) is sufficient to decrease Par-4 levels. These effects are independent of p53, p16 and p19, and were detected not only in fibroblast primary cultures but also in NIH 3T3 and HeLa cells, indicating that they are not secondary to Ras actions on cell cycle regulation. Importantly, restoration of Par-4 levels to normal in Ras-transformed cells makes these cells sensitive to the pro-apoptotic actions of tumor necrosis factor-alpha under conditions in which PI 3-kinase is inhibited and also severely impairs colony formation in soft agar and tumor development in nude mice, as well as increases the sensitivity of these tumors to camptothecin. This indicates that the downregulation of Par-4 by oncogenic Ras is a critical event in tumor progression.

Inactivation of the inhibitory kappaB protein kinase/nuclear factor kappaB pathway by Par-4 expression potentiates tumor necrosis factor alpha-induced apoptosis.

Par-4 is a novel protein identified in cells undergoing apoptosis. The ability of Par-4 to promote apoptotic cell death is dependent on the binding and inactivation of the atypical protein kinases C (PKCs). This subfamily of kinases has been reported to control nuclear factor kappaB (NF-kappaB) through the regulation of the IkappaB kinase activity. NF-kappaB activation by tumor necrosis factor alpha (TNFalpha) provides a survival signal that impairs the TNFalpha-induced apoptotic response. We show here that expression of Par-4 inhibits the TNFalpha-induced nuclear translocation of p65 as well as the kappaB-dependent promoter activity. Interestingly, Par-4 expression blocks inhibitory kappaB protein (IkappaB) kinase activity, which leads to the inhibition of IkappaB phosphorylation and degradation, in a manner that is dependent on its ability to inhibit lambda/iotaPKC. Of potential functional relevance, the expression of Par-4 allows TNFalpha to induce apoptosis in NIH-3T3 cells. In addition, the down-regulation of Par-4 levels by oncogenic Ras sensitizes cells to TNFalpha-induced NF-kappaB activation.

[Informatics and parenteral and enteral nutrition: the state of the art]. / Informática y nutrición parenteral y enteral: estado del arte.

A review was performed of the progress made with the assistance of computers in the parenteral and enteral nutrition field as one more of the many uses made today of the computer industry. Detailed analysis is presented by the authors of the different types of hardware used, as well as the main characteristics and content of the programmes and applications existing in this field, both restricted to small working groups and in management. A comparative study was also made of the management programmes distributed free of charge by some laboratories. Finally, an evaluation was made of the advantages and disadvantages of using computers in parenteral and enteral nutrition at present.