Current Opinion in Cell Biology

Toward unraveling membrane biogenesis in mammalian autophagy.

Publication Date: 2008 May 7 PMID: 18472412
Authors: Yoshimori, T. - Noda, T.
Journal: Curr Opin Cell Biol

Autophagy is a unique form of membrane trafficking, which delivers macromolecules and organelles from the cytoplasm to lysosomes for degradation. This fundamental and ubiquitous process in eukaryotic cells is mediated by the double-membrane-bound structures called autophagosomes, which transiently emerge in the cytoplasm. The recent remarkable explosion of knowledge of autophagy has revealed its multiple roles, especially in mammals; in addition to its basic role in turnover and reuse of cellular constituents, the process unexpectedly functions in elimination of invading bacteria and antigen presentation. Analysis of mammalian homologs of the autophagy-related (Atg) proteins identified in yeast has shed light on not only the common molecular mechanisms underlying autophagosome formation, but also specialized mechanisms that are related to the diverse functions and complex regulation of autophagy in higher organisms.

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Endocytic traffic in animal cell cytokinesis.

Publication Date: 2008 May 7 PMID: 18472411
Authors: Montagnac, G. - Echard, A. - Chavrier, P.
Journal: Curr Opin Cell Biol

Cytokinesis is the final step of mitosis whereby two daughter cells physically separate. It is initiated by the assembly of an actomyosin contractile ring at the mitotic cell equator, which constricts the cytoplasm between the two reforming nuclei resulting in the formation of a narrow intercellular bridge filled with central spindle microtubule bundles. Cytokinesis terminates with the cleavage of the intercellular bridge in a poorly understood process called abscission. Recent work has highlighted the importance of membrane trafficking events occurring from membrane compartments flanking the bridge to the central midbody region. In particular, polarized delivery of endocytic recycling membranes is essential for completion of animal cell cytokinesis. Why endocytic traffic occurs within the intercellular bridge remains largely mysterious and its significance for cytokinesis will be discussed.

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Retromer.

Publication Date: 2008 May 8 PMID: 18472259
Authors: Bonifacino, J. S. - Hurley, J. H.
Journal: Curr Opin Cell Biol

The retromer is a heteropentameric complex that associates with the cytosolic face of endosomes and mediates retrograde transport of transmembrane cargo from endosomes to the trans-Golgi network. The mammalian retromer complex comprises a sorting nexin dimer composed of a still undefined combination of SNX1, SNX2, SNX5 and SNX6, and a cargo-recognition trimer composed of Vps26, Vps29 and Vps35. The SNX subunits contain PX and BAR domains that allow binding to PI(3)P enriched, highly curved membranes of endosomal vesicles and tubules, while Vps26, Vps29 and Vps35 have arrestin, phosphoesterase and alpha-solenoid folds, respectively. Recent studies have implicated retromer in a broad range of physiological, developmental and pathological processes, underscoring the critical nature of retrograde transport mediated by this complex.

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Multifaceted mammalian transcriptome.

Publication Date: 2008 May 9 PMID: 18468878
Authors: Carninci, P. - Yasuda, J. - Hayashizaki, Y.
Journal: Curr Opin Cell Biol

Despite surprisingly a small number of protein-coding gene in mammalian genomes, a large variety of different RNAs is being produced. These RNAs are amazingly different in their number, size, cell localization, and mechanism of actions. Although new classes of short RNAs (sRNAs) are being continuously discovered, it is not yet obvious how many of the sRNAs are originated. Altogether, the research in the recent few years has identified an unexpectedly rich variety of mechanisms by which noncoding RNAs act, suggesting that we have identified probably only few of the many potential functional mechanism and more investigation will be needed to comprehensively understand the complex nature and biology of mammalian RNAome. Here, we focus on various aspects of the diversity of the biological role of these nonprotein-coding RNAs (ncRNAs), with emphasis on functional mechanisms recently elucidated.

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Transcriptional targets of sirtuins in the coordination of mammalian physiology.

Publication Date: 2008 May 9 PMID: 18468877
Authors: Feige, J. N. - Johan, A.
Journal: Curr Opin Cell Biol

Sirtuins (Sirts) compose a family of NAD(+)-dependent deacetylases and/or ADP-ribosyltransferases, which have been implicated in aging, metabolism, and tolerance to oxidative stress. Many of the biological processes regulated by Sirts result from the adaptation of complex gene-expression programs to the energetic state of the cell, sensed through NAD(+) levels. To that respect, Sirts, and particularly the founding member of the family Sirt1, have emerged as important regulators of transcription, which they modulate both positively and negatively by targeting histones and transcriptional complex regulatory proteins. This review will focus on recent advances that have started deciphering how mammalian Sirts regulate transcriptional networks and thereby control physiology.

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Regulation of the sumoylation system in gene expression.

Publication Date: 2008 May 9 PMID: 18468876
Authors: Liu, B. - Shuai, K.
Journal: Curr Opin Cell Biol

Protein sumoylation has emerged as an important regulatory mechanism for the transcriptional machinery. Sumoylation is a highly dynamic process that is regulated in response to cellular stimuli or pathogenic challenges. Altered activity of the small ubiquitin-like modifier (SUMO) conjugation system is associated with human cancers and inflammation. Thus, understanding the regulation of protein sumoylation is important for the design of SUMO-based therapeutic strategies for the treatment of human diseases. Recent studies indicate that the sumoylation system can be regulated through multiple mechanisms, including the regulation of the expression of various components of the sumoylation pathway, and the modulation of the activity of SUMO enzymes. In addition, extracellular stimuli can signal the nucleus to trigger the rapid promoter recruitment of SUMO E3 ligases, resulting in the immediate repression of transcription. Finally, the sumoylation system can also be regulated through crosstalk with other post-translational modifications, including phosphorylation, ubiquitination, and acetylation.

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Intercellular transfer mediated by tunneling nanotubes.

Publication Date: 2008 May 2 PMID: 18456488
Authors: Gerdes, H. H. - Carvalho, R. N.
Journal: Curr Opin Cell Biol

Animal cells have evolved different mechanisms to communicate with one another. In 2004, a new route of cell-to-cell communication mediated by tunneling nanotubes (TNT) was reported. These membranous cell bridges form de novo between cells and mediate the intercellular transfer of organelles, plasma membrane components and cytoplasmic molecules. The characterization of TNT-like bridges from several cell types revealed variations in the cytoskeletal composition as well as in the modality by which they interconnect cells, suggesting that different subclasses may exist. Furthermore, the growing number of cell types for which TNT-like structures were detected, supports the view that they represent a general mechanism for functional connectivity between cells, which could have important implications under physiological conditions.

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Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation.

Publication Date: 2008 Apr 29 PMID: 18450439
Authors: Kraus, W. L.
Journal: Curr Opin Cell Biol

The regulation of gene expression requires a wide array of protein factors that can modulate chromatin structure, act at enhancers, function as transcriptional coregulators, or regulate insulator function. Poly(ADP-ribose) polymerase-1 (PARP-1), an abundant and ubiquitous nuclear enzyme that catalyzes the NAD(+)-dependent addition of ADP-ribose polymers on a variety of nuclear proteins, has been implicated in all of these functions. Recent biochemical, genomic, proteomic, and cell-based studies have highlighted the role of PARP-1 in each of these processes and provided new insights about the molecular mechanisms governing PARP-1-dependent regulation of gene expression. In addition, these studies have demonstrated how PARP-1 functions as an integral part of cellular signaling pathways that culminate in gene-regulatory outcomes.

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Mechanisms involved in the regulation of histone lysine demethylases.

Publication Date: 2008 Apr 25 PMID: 18440794
Authors: Lan, F. - Nottke, A. C. - Shi, Y.
Journal: Curr Opin Cell Biol

Since the first histone lysine demethylase KDM1 (LSD1) was discovered in 2004, a great number of histone demethylases have been recognized and shown to play important roles in gene expression, as well as cellular differentiation and animal development. The chemical mechanisms and substrate specificities have already been extensively discussed elsewhere. This review focuses primarily on regulatory mechanisms that modulate demethylase recruitment and activity.

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Polycomb complexes and epigenetic states.

Publication Date: 2008 Apr 23 PMID: 18439810
Authors: Schwartz, Y. B. - Pirrotta, V.
Journal: Curr Opin Cell Biol

Important advances in the study of Polycomb Group (PcG) complexes in the past two years have focused on the role of this repressive system in programing the genome. Genome-wide analyses have shown that PcG mechanisms control a large number of genes regulating many cellular functions and all developmental pathways. Current evidence shows that, contrary to the classical picture of their role, PcG complexes do not set a repressed chromatin state that is maintained throughout development but have a much more dynamic role. PcG target genes can become repressed or be reactivated or exist in intermediate states. What controls the balance between repression and derepression is a crucial question in understanding development and differentiation in higher organisms.

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Functional integration of transcriptional and RNA processing machineries.

Publication Date: 2008 Apr 22 PMID: 18436438
Authors: Pandit, S. - Wang, D. - Fu, X. D.
Journal: Curr Opin Cell Biol

Cotranscriptional RNA processing not only permits temporal RNA processing before the completion of transcription but also allows sequential recognition of RNA processing signals on nascent transcripts threading out from the elongating RNA polymerase II (RNAPII) complex. Rapid progress in recent years has established multiple contacts that physically connect the transcription and RNA processing machineries, which centers on the C-terminal domain (CTD) of the largest subunit of RNAPII. Although cotranscriptional RNA processing has been substantiated, the evidence for 'reciprocal' coupling starts to emerge, which emphasizes functional integration of transcription and RNA processing machineries in a mutually beneficial manner for efficient and regulated gene expression.

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The RNA polymerase II core promoter - the gateway to transcription.

Publication Date: 2008 Apr 22 PMID: 18436437
Authors: Juven-Gershon, T. - Hsu, J. Y. - Theisen, J. W. - Kadonaga, J. T.
Journal: Curr Opin Cell Biol

The RNA polymerase II core promoter is generally defined to be the sequence that directs the initiation of transcription. This simple definition belies a diverse and complex transcriptional module. There are two major types of core promoters - focused and dispersed. Focused promoters contain either a single transcription start site or a distinct cluster of start sites over several nucleotides, whereas dispersed promoters contain several start sites over 50-100 nucleotides and are typically found in CpG islands in vertebrates. Focused promoters are more ancient and widespread throughout nature than dispersed promoters; however, in vertebrates, dispersed promoters are more common than focused promoters. In addition, core promoters may contain many different sequence motifs, such as the TATA box, BRE, Inr, MTE, DPE, DCE, and XCPE1, that specify different mechanisms of transcription and responses to enhancers. Thus, the core promoter is a sophisticated gateway to transcription that determines which signals will lead to transcription initiation.

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