Cell Death & Differentiation

Melino, G; Nicotera, P; Macino, G

doi: 10.1038/sj.cdd.4402259pmid: 18007667

Kornberg, R D

doi: 10.1038/sj.cdd.4402250pmid: 18007668

Mello, C C

doi: 10.1038/sj.cdd.4402249pmid: 18007669

Knott, A B; Bossy-Wetzel, E

doi: 10.1038/sj.cdd.4402241pmid: 17917678

Kornberg, R D

doi: 10.1038/sj.cdd.4402251pmid: 18007670

Thanks to the Nobel Foundation for permission to publish this Lecture (Copyright© The Nobel Foundation 2006). We report here the Nobel Lecture delivered by Professor RD Kornberg describing his research in the understanding of transcription in eucaryotes. The amazing work by Professor Kornberg goes from the discovery of the nucleosome to the structural and functional studies of pol II transcription complexes. His research sheds light on fundamental molecular biology problems such as transcription initiation, fidelity of transcription, RNA release at the end of transcription, and many more. This is a beautiful report on how structural and functional studies can be combined to really understand in an accurate and detailed way how proteins combine in huge molecular complexes to regulate one of the most important cellular processes: gene transcription.

Fire, A Z

doi: 10.1038/sj.cdd.4402253pmid: 18007671

The December 2007 article labelled as Dr. Andrew Fire's Nobel Lecture "Gene Silencing By Double Stranded RNA" was an abridged version that was prepared and published by Cell Death and Differentiation with the consent of the Nobel Foundation but without Dr. Fire's knowledge or consent. The Nobel Foundation did not explicitly give permission for it to be edited, and the editors have withdrawn the abridged article from the Cell Death and Differentiation archive. Readers can download the original and complete version of Dr. Fire's Nobel Lecture at the Nobel Foundation website: http://nobelprize.org/nobel_prizes/medicine/laureates/2006/fire-lecture.html

Mello, CC

doi: 10.1038/sj.cdd.4402252pmid: 18007672

Thanks to the Nobel Foundation for permission to publish this Lecture (Copyright© The Nobel Foundation 2006). Here we report the transcript of the lecture delivered by Professor Craig C Mello at the Nobel Prize ceremony. Professor Mello vividly describes the years of research that led to the discovery of RNA interference and the molecular mechanisms that regulate this fundamental cellular process. The turning point of discoveries and the role played by all his colleagues and collaborators are described, making this a wonderful report of the adventure of research. The lecture explains in simple language the importance of this discovery that has added a great level of complexity to the way cells regulate protein levels; moreover, it points out the beauty and importance of Caenorhabditis elegans as a model organism and how the use of this model has greatly contributed to the advance of science. Finally, Professor Mello leaves us with a number of questions that his research has raised and that will require years of future research to be answered.

Berg, D; Lehne, M; Müller, N; Siegmund, D; Münkel, S; Sebald, W; Pfizenmaier, K; Wajant, H

doi: 10.1038/sj.cdd.4402213pmid: 17703232

Variants of human TRAIL (hTRAIL) and human CD95L (hCD95L), encompassing the TNF homology domain (THD), interact with the corresponding receptors and stimulate CD95 and TRAILR2 signaling after cross-linking. The murine counterparts (mTRAIL, mCD95L) showed no or only low receptor binding and were inactive/poorly active after cross-linking. The stalk region preceding the THD of mCD95L conferred secondary aggregation and restored CD95 activation in the absence of cross-linking. A corresponding variant of mTRAIL, however, was still not able to activate TRAIL death receptors, but gained good activity after cross-linking. Notably, disulfide-bonded fusion proteins of the THD of mTRAIL and mCD95L with a subdomain of the tenascin-C (TNC) oligomerization domain, which still assembled into trimers, efficiently interacted with their cognate cellular receptors and robustly stimulated CD95 and TRAILR2 signaling after secondary cross-linking. Introduction of the TNC domain also further enhanced the activity of THD encompassing variants of hTRAIL and hCD95L. Thus, spatial fixation of the N-terminus of the THD appears necessary in some TNF ligands to ensure proper receptor binding. This points to yet unanticipated functions of the stalk and/or transmembrane region of TNF ligands for the functionality of these molecules and offers a broadly applicable option to generate recombinant soluble ligands of the TNF family with superior activity.

Hu, Y; Liu, Z; Yang, S-J; Ye, K

doi: 10.1038/sj.cdd.4402214pmid: 17721436

Histone H2B phosphorylation tightly correlates with chromatin condensation during apoptosis. The caspase-cleaved acinus (apoptotic chromatin condensation inducer in the nucleus) provokes chromatin condensation in the nucleus, but the molecular mechanism accounting for this effect remains elusive. Here, we report that the active acinus p17 fragment initiates H2B phosphorylation and chromatin condensation by activating protein kinase C δ isoform (PKC-δ). We show that p17 binds to both Mst1 and PKC-δ, which is upregulated by apoptotic stimuli, enhancing their kinase activities. Acinus mutant susceptible to degradation elicits stronger chromatin condensation and higher H2B phosphorylation than wild-type acinus. Dominant-negative PKC-δ but not Mst1 robustly blocks acinus-initiated H2B phosphorylation. Surprisingly, depletion of Mst1 triggers caspase-3 activation, provoking H2B phosphorylation through activating PKC-δ. Further, acinus-elicited H2B phosphorylation and chromatin condensation are abrogated in PKC-δ-deficient mouse embryonic fibroblast cells and siRNA-knocked down PC12 cells. Thus, PKC-δ but not Mst1 acts as a physiological downstream kinase of acinus in promoting H2B phosphorylation and chromatin condensation.

Benosman, S; Gross, I; Clarke, N; Jochemsen, A G; Okamoto, K; Loeffler, J-P; Gaiddon, C

doi: 10.1038/sj.cdd.4402216pmid: 17823617

MDMX has been shown to modulate p53 in dividing cells after DNA damage. In this study, we investigated the role of MDMX in primary cultures of neurons undergoing cell death. We found that DNA damage, but also membrane-initiated apoptotic stresses (glutamate receptor; Amyloid β precursor) or survival factor deprivation downregulated MDMX protein levels. Forced downregulation of murine double minute X (MDMX) by shRNA induced apoptosis suggesting that MDMX is required for survival in neurons. Protease inhibitors prevented the loss of MDMX after neurotoxic treatments, indicating a regulation of protein stability. Some, but not all, neurotoxic stresses induced phosphorylation of MDMX at serine 367, further supporting regulation at the protein level. Interestingly, we found that depending on the stimulus either p53 or E2F1 was induced, but overexpression of MDMX inhibited the transcriptional activity of both proapoptotic factors, and maintained neuronal viability upon neurotoxic stresses. Taken together, our data show that MDMX is an antiapoptotic factor in neurons, whose degradation is induced by various stresses and allows activation of p53 and E2F-1 during neuronal apoptosis.