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- Editorial Board
- Trends Cell Biol 19(8):i (2009)
- Novel ubiquitin-dependent quality control in the endoplasmic reticulum
Feldman M Gisou van der Goot F - Trends Cell Biol 19(8):357-363 (2009)
Proteins of the endomembrane system undergo assisted folding in the endoplasmic reticulum (ER), then quality-control and, if misfolded, ER-associated degradation (ERAD). Recent findings on the biogenesis of a type-I membrane protein (an LRP6 mutant) lead us to hypothesize the existence of a novel mechanism promoting folding of membrane proteins from the cytosolic side of the ER. The proposed folding mechanism involves cycles of chaperone binding through mono-ubiquitylation and de-ubiquitylation, followed eventually by poly-ubiquitylation and ERAD. This suggests a novel dual role for ubiquitylation in the ER – dependent on the type of ubiquitin chains involved – in folding and in degradation, and highlights the potential importance of de-ubiquitylating enzymes.
- Scaffolds: interaction platforms for cellular signalling circuits
Zeke A Lukács M Lim WA Reményi A - Trends Cell Biol 19(8):364-374 (2009)
Scaffold proteins influence cellular signalling by binding to multiple signalling enzymes, receptors or ion channels. Although normally devoid of catalytic activity, they have a big impact on controlling the flow of signalling information. By assembling signalling proteins into complexes, they play the part of signal processing hubs. As we learn more about the way signalling components are linked into natural signalling circuits, researchers are becoming interested in building non-natural signalling pathways to test our knowledge and/or to intentionally reprogram cellular behaviour. In this review, we discuss the role of scaffold proteins as efficient tools for assembling intracellular signalling complexes, both natural and artificial.
- The spliceosome: a self-organized macromolecular machine in the nucleus?
Rino J Carmo-Fonseca M - Trends Cell Biol 19(8):375-384 (2009)
In higher eukaryotes, the vast majority of protein-coding genes contain introns that must be removed from precursor mRNA (pre-mRNA) with great precision by the spliceosome. Spliceosomes are massive RNA–protein macromolecular machines with >100 distinct components that assemble onto nascent transcripts and are released from the mRNA after splicing. A large and longstanding body of biochemical evidence indicates that the spliceosome is constructed de novo for each round of splicing in an ordered piece-by-piece stepwise assembly. More recently, exciting advances in intracellular imaging approaches are providing new clues to understand the dynamic organization of this and other multi-component molecular machines in the nucleus. The emerging data suggest that stochastic interactions between spliceosomal proteins originate intermediate complexes that localize in the close vicinity of active genes, thus contributing to increase the local availability of the individual piece! s required for assembly of functional spliceosomes on newly synthesized pre-mRNA.
- New regulatory mechanisms of TGF-β receptor function
- Trends Cell Biol 19(8):385-394 (2009)
Transforming growth factor-β (TGF-β) regulates cell proliferation, differentiation and apoptosis, and TGF-β-related proteins have key roles in development, tissue homeostasis and disease. Upon binding to their cell surface receptors, TGF-β family proteins signal through Smads to induce changes in gene expression. TGF-β-induced Smad signaling and additional non-Smad pathways have been studied extensively in an effort to understand the complex and versatile responses to TGF-β family proteins. Recently, it has become increasingly apparent that the signaling responses are also extensively defined by regulatory mechanisms at the level of the receptors themselves. Here, we discuss recent insights into the effects of post-translational modifications, protein associations and mode of internalization on the functions of the TGF-β receptors and their signaling responses.
- Neurofibroma development in NF1 – insights into tumour initiation
Parrinello S Lloyd AC - Trends Cell Biol 19(8):395-403 (2009)
Dissecting the early steps of tumourigenesis is key to our understanding of cancer biology. However, lack of knowledge of initiating mutations and the target 'cell of origin' has slowed progress towards this goal. Genetically engineered mouse models of the tumour-predisposition syndrome neurofibromatosis type-1 provide a rare opportunity to study tumour initiation resulting from a known genetic change in a known cell type. Recent exciting work using these models now sheds more light onto early tumourigenesis. Here, we discuss the studies that have identified mature differentiated Schwann cells as the cell of origin and revealed the molecular and cellular mechanisms of neurofibroma initiation. A novel dual and opposing role for the microenvironment, from pro-differentiative to pro-carcinogenic, has emerged.
- The NF-κB-independent functions of IKK subunits in immunity and cancer
- Trends Cell Biol 19(8):404-413 (2009)
The IκB kinase (IKK) complex is involved in transcriptional activation by phosphorylating the inhibitory molecule IκBα, a modification that triggers its subsequent degradation, enabling activation of nuclear factor kappa B (NF-κB). Importantly, recent reports indicate that multiple cytoplasmic and nuclear proteins distinct from the NF-κB and IκB proteins are phosphorylated by the catalytic subunits of the IKK complex, IKKα or IKKβ. Here, I describe how IKK subunits can have crucial roles in allergy, inflammation and immunity by targeting proteins such as SNAP23 and IRF7, but also in cancer by phosphorylating key molecules such as p53, TSC1 and FOXO3a through NF-κB-independent pathways. Thus, these recent findings considerably widen the biological roles of these kinases and suggest that a full understanding of the biological roles of IKKα and IKKβ requires an exhaustive characterization of their substrates.
- G-quadruplex structures: in vivo evidence and function
- Trends Cell Biol 19(8):414-422 (2009)
Although many biochemical and structural studies have demonstrated that DNA sequences containing runs of adjacent guanines spontaneously fold into G-quadruplex DNA structures in vitro, only recently has evidence started to accumulate for their presence and function in vivo. Genome-wide analyses have revealed that functional genomic regions from highly divergent organisms are enriched in DNA sequences with G-quadruplex-forming potential, suggesting that G-quadruplexes could provide a nucleic-acid-based mechanism for regulating telomere maintenance, as well as transcription, replication and translation. Here, we review recent studies aimed at uncovering the in vivo presence and function of G-quadruplexes in genomes and RNA, with a particular focus on telomeric G-quadruplexes and how their formation and resolution is regulated to permit telomere synthesis.