Smac/DIABLO se fosforila

Phosphorylation of Smac by JNK3 attenuates its interaction with XIAP.

Biochem Biophys Res Commun. 2007 Jul 31;

Authors: Park BD, Ham YM, Jeong HJ, Cho SJ, Je YT, Yoo KD, Lee SK

Here we demonstrate that JNK3 can phosphorylate Smac. Smac phosphorylation attenuates its ability to activate apoptosome activity in HeLa S-100 cell lysates. Addition of the X-linked inhibitor of apoptosis protein (XIAP) to the S-100 markedly suppresses apoptosome activity, and this suppressive effect of XIAP is neutralized by adding unphosphorylated Smac, but not phosphorylated Smac. Furtherover, JNK3-mediated phosphorylation of Smac markedly attenuates the interaction between Smac and XIAP, as measured by BIACORE assays and non-denaturing gel shift assays. When JNK3 activity is down-regulated in etoposide-induced HeLa cells by transiently overexpressing a dominant negative version of JNK3 (DN-JNK3), the caspase-3 activity as well as PARP cleavages are markedly enhanced. And the interaction of Smac with XIAP also increases by down-regulating JNK3 activity under the same conditions. These results suggest that JNK3 activity can attenuate the progression of apoptosis through a novel mechanism of action, the down-regulation of interaction between Smac and XIAP

p53. Efectos supresores independientes de apoptosis?

Una hipotesis muy arraigada es que la capacidad de p53 para suprimir tumores de p53 esta mediada por su habilidad para inducir apoptosis en celulas que tienen su ADN dañado. Este nuevo articulo contribuye a la idea de que esto no es universal, y que pueden existir tumores especificos en donde p53 suprime por otro mecanismo:

Nature Medicine 13, 992 - 997 (2007)
David G Kirsch

A spatially and temporally restricted mouse model of soft tissue sarcoma

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.
Por ende, p53 emplea otro mecanismo de supresion en el caso de estos sarcomas

Otro nivel de control para las IAPs

Para evitar que las celulas mueran por apoptosis por la actividad incontrolada de las caspasas, existe una familia de proteinas inhibidoras conocidas como IAPs:


Las IAPs incluyen proteinas tan importantes como la survivina (en la que trabaja Magali). Su mecanismo de control en general esta mediado por sintesis de novo, es decir, a nivel transcripcional. Sin embargo este nuevo articulo de D. Altieri, muestra que es posible regular a estas proteinas mediante fosforilacion, en particular por PKA (protein cinasa activada por AMPc). Es interesante destacar que Moises, un alumno nuestro de doctorado, encontro que la PKA, inducida por el AMPc, fosforila a CREB para incrementar la transcripcion de Smac/DIABLO que a su vez induce apoptosis (resumen articulo). Esto explicaba parcialmente la capacidad apoptotica del AMPc. Si sumamos a esto que la PKA fosforila a la survivina citosolica (no mitocondrial) y la inhibe, tenemos dos mecanismos sinergicos para inducir apoptosis. Asimismo, esto añade otra dimensión al trabajo de Gisela, otra alumna nuestra, que encontro que la survivina mitocondrial puede evitar la salida de Smac/DIABLO de este organelo. Esto sugeriria que, de ser regulado, el mecanismo de importacion de la Survivina a la mitocondria podria ser importante para la apoptosis y para determinar el umbral a las drogas antineoplasicas.