TRAIL induce el corte de p65 por caspasa 3 para inducir apoptosis

Este articulo es interesante. Plantea un nuevo mecanismo de TRAIL para bloquear la activacion de NFkB y permitir la apoptosis. Este es el corte de p65 por caspasa 3. Esto pasa en HeLa y HEK293. Como situacion adicional, la expresion de XIAP es regulada por suero y si esta a concentracion normal no ven los cambios de expresion mediados por NFkB (gisela)
Caspase-mediated p65 cleavage promotes TRAIL-induced apoptosis.
Cancer Res. 2005 Jul 15;65(14):6111-9
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is cytotoxic to a wide variety of transformed cells, but not to most normal cells, implying potential therapeutic value against advanced cancer. However, signal transduction in TRAIL-mediated apoptosis is not clearly understood compared with other TNF family members. Specifically, it is not yet understood how TRAIL controls nuclear factor kappaB (NF-kappaB) activation and overcomes its anti-apoptotic effect. We explored the regulation of NF-kappaB activity by TRAIL and its role in apoptosis. TRAIL combined with IkappaBalpha-"superrepressor" induced potent apoptosis of SK-Hep1 hepatoma cells at low concentrations of TRAIL that do not independently induce apoptosis. Apoptosis by high concentrations of TRAIL was not affected by IkappaBalpha-superrepressor. Although TRAIL alone did not induce NF-kappaB activity, TRAIL combined with z-VAD significantly increased NF-kappaB activation. Analysis of the NF-kappaB activation pathway indicated that TRAIL unexpectedly induced cleavage of p65 at Asp97, which was blocked by z-VAD, accounting for all of these findings. p65 expression abrogated apoptosis and increased NF-kappaB activity in TRAIL-treated cells. Cleavage-resistant p65D97A further increased NF-kappaB activity in TRAIL-treated cells, whereas the COOH-terminal p65 fragment acted as a dominant-negative inhibitor. XIAP levels were increased by TRAIL in combination with z-VAD, whereas XIAP levels were decreased by TRAIL alone. Cleavage of p65 was also detected after FRO thyroid cancer cells were treated with TRAIL. These results suggest that TRAIL induces NF-kappaB activation, but simultaneously abrogates NF-kappaB activation by cleaving p65, and thereby inhibits the induction of anti-apoptotic proteins such as XIAP, which contributes to the strong apoptotic activity of TRAIL compared with other TNF family members.

IKK1 vs IKK2?

IKK1 podria ser antagonista de la activacion de NFkB. Esto coincide con papers previos en los que los niveles relativos de IKK1 y 2 determinaban la activacion de NFkB y un articulo previo de IKK1 como inhibidor en macrofagos. En el caso del TIMP seria interesante analizar los niveles de ambas.

Zebrafish IκB Kinase 1 Negatively Regulates NF-κB Activity Ricardo G. Correa, Takaaki Matsui Vinay Tergaonkar, Concepcion Rodriguez-Esteban, Juan Carlos Izpisua-Belmonte and Inder M. Verma. Curr. Biol. 15: 26 July 2005, Pages 1291-1295
The IκB kinase (IKK) activity is critical for processing IκB inhibitory proteins and activating the NF-κB signaling, which is involved in a series of physiological and developmental steps in vertebrates [1, 2, 3 and 4]. The IKK activity resides in two catalytic subunits, IKK1 and IKK2, and two regulatory subunits, NEMO and ELKS [5, 6, 7 and 8]. IKK2 is the major cytokine-responsive IκB kinase [9, 10 and 11] because depletion of IKK1 does not interfere with the IKK activity [12, 13 and 14]. In fact, IKK1^−/− mice display morphological abnormalities that are independent of its kinase activity and NF-κB activation [12, 13 and 14]. Hence, using zebrafish (Danio rerio) as a model, we examined the evolutionary role of IKK1 in modulating NF-κB. Ikk1^−/− zebrafish embryos present head and tail malformations and, surprisingly, show upregulation of NF-κB-responsive genes and increased NF-κB-dependent apoptosis. Overexpression of ikk1 leads to midline structure defects that resemble NF-κB blockage in vivo [1]. Zebrafish Ikk1 forms complexes with NEMO that represses NF-κB in vertebrate cells. Indeed, truncation of its NEMO binding domain (NBD) restores NF-κB-dependent transcriptional activity and, consequently, the ikk1-overexpressing phenotype. Here, we report that Ikk1 negatively regulates NF-κB by sequestering NEMO from active IKK complexes, indicating that IKK1 can function as a repressor of NF-κB.

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Papilomavirus induce la expresion de IAP-2

Nuevo articulo publicado en oncogene describe la sobreexpresion de IAP-2 mediada por E6 y E7. Podria ser un marcador?

Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis Huidong Yuan, Fenghua Fu, Jiaying Zhuo, Wei Wang, Junko Nishitani, Dong Sung An, Irvin S Y Chen and Xuan Liu Oncogene 24: 5069-5078; advance online publication, April 25, 2005

nhibition of apoptosis plays an important role in the cellular immortalization and transformation induced by E6 and E7 oncoproteins of human papillomavirus (HPV). Here, we report that the transcription of the inhibitor of apoptosis gene, cellular inhibitor of apoptosis protein 2, (c-IAP2), is significantly upregulated in HPV16 E6/E7-immortalized human oral keratinocytes (HOK16E6E7). Overexpression of E6/E7 from the high-risk HPV16 or 18, but not from the low-risk HPV6, activated c-IAP2 promoter. E6 from HPV16 and 18 played a major role in the activation. In addition, the induction of c-IAP2 transcription required nuclear factor-B activity. Overexpression of c-IAP2 in normal human oral keratinocyte conferred resistance to tumor necrosis factor- (TNF-)/cycloheximide (CHX)-induced apoptosis, suggesting the increased c-IAP2 expression in HOK16E6E7 may protect the cells from TNF--mediated cell death. Moreover, depletion of endogenous c-IAP2 using RNA interference in HOK16E6E7 induced apoptosis, indicating that c-IAP2 is necessary for HPV16 E6/E7-induced resistance to apoptosis and cell survival. Of note, high levels of c-IAP2 transcription were found in several HPV16- or HPV18-positive cancer cells, and depletion of c-IAP2 caused cell death in HPV18-positive HeLa cells. Thus, upregulation of c-IAP2 by E6 and E7 may confer resistance to apoptosis that is necessary for sustained growth of some HPV16- and HPV18-positive cancer cells.

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Elemento faltante

Este es un articulo importante. Las IAPs (en particular XIAP) son las inhibidoras naturales de las caspasas efectoras y la caspasa 9, de la via intrinseca. Sin embargo no existian las contrapartes de las caspasas de la via extrinseca. Algunos pensaban que la modulacion era mediada solo por FLIP, una proteina parecida a c. 8 sin actividad proteolitica. Sin embargo, El-Deiry identifico a las CARP 1 y 2 como las equivalentes a las IAPs en la via extrinseca. Las CARP habian sido identificadas antes como RHF1, un gen que estaba sobreexpresado en cancer de esofago, pero para el que no tenian funcion (esto no viene en el articulo). Ya tenemos primers de CARP1, que funcionan bien.
Suppression of caspase-8- and -10-associated RING proteins results in sensitization to death ligands and inhibition of tumor cell growth. Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6170-5
The destruction of cellular targets during apoptosis is carried out by caspases, which are negatively regulated by the inhibitor of apoptosis proteins (IAP); however, death effector domain (DED) caspases of the extrinsic pathway are refractory to the IAP family. We have isolated a family of apoptotic inhibitors [caspases-8- and -10-associated RING proteins (CARPs)] that bind to and negatively regulate DED caspases. When overexpressed, CARPs, via an IAP-like RING domain, can contribute to the ubiquitin-mediated proteolysis of DED caspases. Furthermore, CARPs are rapidly cleaved during apoptosis. However, in tumors and tumor cell lines, they are overexpressed, and their silencing leads to restoration of efficient apoptosis via enhanced activation of DED caspases. Long-term inhibition of CARP expression results in suppression of cancer cell growth, highlighting their importance in tumor cell survival.
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Revision de apoptosis intrinseca

Apoptotic pathways: ten minutes to dead.
Cell. 2005 Jun 3;121(5):671-4. Review.
For more than a decade, it has been apparent that apoptosis and other forms of cell death are often controlled at one or more crucial steps involving the mitochondria. Recent findings, including an elegant investigation in a recent issue of Cell (Hao et al., 2005), have helped to elucidate fundamental aspects of this involvement while raising puzzling new questions about mitochondrial routes to cellular demise. The emerging, if preliminary, perspective these new studies provide may represent either a refinement of our views of how cells die or, perhaps, the beginnings of what amounts to a reformulation of our ideas.
Yo diria que la mejor revision de los ultimos dos años en este tema. Me gustaria que todos lo leyeran, sobre todo por nuestro resultados de smac y lo que planeo hacer a continuacion.
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Revision de checkpoint mitotico

Minireview

Decoding the links between mitosis, cancer, and chemotherapy: The mitotic checkpoint, adaptation, and cell death
Beth A.A. Weaver¹ and Don W. Cleveland
Cancer Cell, Vol 8, 7-12, July 2005
Disrupted passage through mitosis often leads to chromosome missegregation and the production of aneuploid progeny. Aneuploidy has long been recognized as a frequent characteristic of cancer cells and a possible cause of tumorigenesis. Drugs that target mitotic spindle assembly are frequently used to treat various types of human tumors. These lead to chronic mitotic arrest from sustained activation of the mitotic checkpoint. Here, we review the linkage between the mitotic checkpoint, aneuploidy, adaptation from mitotic arrest, and antimitotic drug-induced cell death.
Importante para revisar, sobre todo ruben, por lo de la crisis mitotica

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Epithelial-mesenchymal transition (EMT)

The new study shows that one type, MMP-3, causes normal cells to express a protein, Rac1b, that has previously been found only in cancers. Rac1b stimulates the production of highly reactive oxygen molecules, which promote cancer in two ways — by leading to tissue disorganization and by damaging genomic DNA. Changes in the cell skeleton induced by Rac1b trigger the formation of extremely reactive molecules known as reactive oxygen species, or ROS. In turn, the increased amount of ROS activates key genes that control the epithelial-mesenchymal transition — the first slippage in an avalanche of tissue disorganization.
"MMP-3-induced Rac1b stimulates formation of ROS, causing EMT and genomic instability," by Derek C. Radisky, Dinah D. Levy, Laurie E. Littlepage, Hong Liu, Celeste M. Nelson, Jimmie E. Fata, Devin Leake, Elizabeth L. Godden, Donna G. Albertson, M. Angela Nieto, Zena Werb, and Mina J. Bissell, appears in the 7 July 2005 issue of Nature.
Interesante por el hecho de que la modificacion externa, mediada por el estroma, puede incidir en la progresion del cancer. Cubre un vacio en el papel de la estromelisina en el cancer de mama.

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Caspase-independent cell death

Una nueva revision publicada en Nature Medicine 11, 725 - 730 (2005) de G. Kroemer (el de AIF)
Caspase activation has been frequently viewed as synonymous with apoptotic cell death; however, caspases can also contribute to processes that do not culminate in cell demise. Moreover, inhibition of caspases can have cytoprotective effects. In a number of different models, caspase inhibition does not maintain cellular viability and instead shifts the morphology of death from apoptosis to nonapoptotic pathways. Here, we explore the contribution of caspases to cell death, either as upstream signals or as downstream effectors contributing to apoptotic morphology, as well as alternative strategies for cell death inhibition. Such alternative strategies may either target catabolic hydrolases or be aimed at preventing mitochondrial membrane permeabilization and its upstream triggers

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