Journal of Molecular Cell Biology - recent issues

Macrophage Metalloelastase: Stretching Therapeutic Opportunities

He, J. Q., van Lookeren Campagne, M. — Fri, 20 Nov 2009 07:56:31 PST

While tissue macrophages are at the first line of microbial host defense, they are also convenient hideouts for pathogens escaping immune attack. Houghton et al. discovered that alveolar macrophage mobilizes macrophage metalloelastase to destroy bacteria present inside the cell.

Cohesin: A Multi-purpose Chromatin Glue

Diaz-Martinez, L. A., Yu, H. — Fri, 20 Nov 2009 07:56:31 PST

Long thought to be the glue responsible for holding sister chromatids together, cohesin has been found to be stickier than previously thought. Recent discoveries point to cohesin having a role in transcription regulation by mediating long-distance intra-chromosomal interactions.

Dynamic Balancing: DEPTOR Tips the Scales

Proud, C. G. — Fri, 20 Nov 2009 07:56:31 PST

The mammalian target of rapamycin, mTOR, is a key node in cellular regulation: its dysregulation is important in a number of disease states, including various cancers. A recent study identifies a new partner and regulator of mTOR, which can alter the balance of signaling downstream of mTOR and appears to be important in certain cancers, such as multiple myelomas.

When Shigella Tells the Cell to Hang On

Tran Van Nhieu, G., Guignot, J. — Fri, 20 Nov 2009 07:56:31 PST

OspE, a Shigella type III effector binds to integrin-like kinase and enhances cell adhesion to better disseminate and colonize the intestinal epithelium. Because of the existence of OspE orthologues in other enteropathogens such as enteropathogenic Escherichia coli or Salmonella sp., maintenance of cell adhesion appears as a widespread strategy for bacteria that interact with the intestinal epithelium.

BATF: Bringing (in) Another Th17-regulating Factor

Martinez, G. J., Dong, C. — Fri, 20 Nov 2009 07:56:31 PST

T helper (Th) 17 cells are a recently identified subset of T cells that regulate tissue inflammation, and RORt and ROR have been shown to be Th17-specific transcription factors that mediate Th17 cell generation. A new study of Batf-deficient mice shows that this AP-1 family transcription factor also regulates Th17 cell differentiation by binding to Th17-associated gene promoters and by maintaining ROR and RORt expression, shedding new lights on current clinical modulation of Th17 cell function in inflammatory diseases.

The Emergence of Basophils as Antigen-Presenting Cells in Th2 Inflammatory Responses

Mikhak, Z., Luster, A. D. — Fri, 20 Nov 2009 07:56:31 PST

Basophils gain prominence in Th2 inflammatory responses with the discovery that they function as antigen-presenting cells and are sufficient to drive Th2 cell differentiation.

A Pom1 Gradient Is Made to Measure

Calvert, M. E. — Fri, 20 Nov 2009 07:56:31 PST

In order for cell division to proceed, fission yeast must first attain critical cell size. The mechanism by which size is detected had not been identified until two recent studies showed that cells utilize an intracellular gradient of Pom1p kinase to measure cell length.

Cholesterol Worships a New Idol

Schulman, I. G. — Fri, 20 Nov 2009 07:56:31 PST

The growing worldwide epidemic of cardiovascular disease suggests that new therapeutic strategies are needed to complement statins in the lowering of cholesterol levels. In a recent paper in Science, Tontonoz and colleagues have identified Idol as a protein that can control cholesterol levels by regulating the stability of the low-density lipoprotein receptor; inhibiting the activity of Idol could provide novel approaches for the treatment of cardiovascular disease.

Innate Immune Cells Cast an Eye on DNA

Sander, L. E., Blander, J. M. — Fri, 20 Nov 2009 07:56:31 PST

The threonine phosphatase eyes absent (EYA) has been identified as a novel regulator of innate immune responses to cytosolic nucleic acids and undigested DNA from apoptotic cells. EYA regulates responses of yet unidentified DNA sensors and enhances interferon-β and CXCL10 transcription.

Another Facet of Ubiquitylation: Death

Wong, W. W.-L., Silke, J. — Fri, 20 Nov 2009 07:56:31 PST

Ubiquitylation of caspase-8 by the Cullin3 E3 ligase allows its translocation to cytosolic aggregates in the cell by p62/sequestosome-1, increasing caspase-8 activation and thus leading to TRAIL-induced cell death.

The TET Family of Proteins: Functions and Roles in Disease

Tan, A. Y., Manley, J. L. — Fri, 20 Nov 2009 07:56:31 PST

Translocated in liposarcoma, Ewing's sarcoma and TATA-binding protein-associated factor 15 constitute an interesting and important family of proteins known as the TET proteins. The proteins function in several aspects of cell growth control, including multiple different steps in gene expression, and they are also found mutated in a number of specific diseases. For example, all contain domains for binding nucleic acids and have been shown to function in both RNA polymerase II-mediated transcription and pre-mRNA splicing, possibly connecting these two processes. Chromosomal translocations in human sarcomas result in a fusion of the amino terminus of these proteins, which contains a transcription activation domain, to the DNA-binding domain of a transcription factor. Although the fusion proteins have been characterized in a clinical environment, the function of the cognate full-length protein in normal cells is a more recent topic of study. The first part of this review will describe the TET proteins, followed by detailed descriptions of their multiple roles in cells. The final sections will examine changes that occur in gene regulation in cells expressing the fusion proteins. The clinical implications and treatment of sarcomas will not be addressed but have recently been reviewed.

Dazl Promotes Germ Cell Differentiation from Embryonic Stem Cells

Yu, Z., Ji, P., Cao, J., Zhu, S., Li, Y., Zheng, L., Chen, X., Feng, L. — Fri, 20 Nov 2009 07:56:31 PST

It has been demonstrated that through the formation of embryoid bodies (EBs) germ cells can be derived from embryonic stem (ES) cells. Here, we describe a transgene expression approach to derive germ cells directly from ES cells in vitro without EB formation. Through the ectopic expression of Deleted in Azoospermia-Like (Dazl), a germ cell-specific RNA-binding protein, both motile tailed-sperm and oocytes were induced from mouse ES (mES) cells in culture. Furthermore, transient overexpression of Dazl led to suppression of Nanog but induced germ cell nuclear antigen in mES cells. Dazl knockdown resulted in reduction in the expression of germ cell markers including Stella, MVH and Prdm1. Our study indicates that Dazl is a master gene controlling germ cell differentiation and that ectopic expression of Dazl promotes the dynamic differentiation of mouse ES cells into gametes in vitro.

JMCB: From China, for the World

Li, D. — Fri, 25 Sep 2009 08:13:40 PDT

From Breast to the Brain: Unraveling the Puzzle of Metastasis Organotropism

Hu, G., Kang, Y., Wang, X.-F. — Fri, 25 Sep 2009 08:13:40 PDT

Metastatic colonization of different target organs is a highly selective process that depends on specialized properties of tumor cells. In a recent Nature paper, Massagué and colleagues built on their earlier success in functional genomic analysis of breast cancer metastasis to bone and lung and reported the identification of breast cancer brain metastasis genes, highlighting the importance of the stromal environment in the development of organ-specific metastasis.

Acute Lung Injury: A Yellow Card for Engineered Nanoparticles?

Liu, M., Zhang, H., Slutsky, A. S. — Fri, 25 Sep 2009 08:13:40 PDT

Application of nanomaterials in various diagnostic and therapeutic areas shows great promise. To translate nanotechnology into nanomedicine, it is important to understand any potential mechanisms of toxicity caused by nanomaterials, and to design approaches to mitigate any detrimental effects.

RIP Kinases Initiate Programmed Necrosis

Galluzzi, L., Kepp, O., Kroemer, G. — Fri, 25 Sep 2009 08:13:40 PDT

Some lethal stimuli can induce either apoptosis or necrosis, depending on the cell type and/or experimental setting. Until recently, the molecular bases of this phenomenon were largely unknown. Now, two members of the receptor-interacting serine-threonine kinase (RIP) family, RIP1 and RIP3, have been demonstrated to control the switch between apoptotic and necrotic cell death. Some mechanistic details, however, remain controversial.

A Little Bit of Sugar Makes Polycomb Better

Schwartz, Y. B., Pirrotta, V. — Fri, 25 Sep 2009 08:13:40 PDT

Transcriptional repression by Polycomb group (PcG) proteins is now sweetened by the discovery of the essential role of O-GlcNAc glycosylation in the process. PcG protein polyhomeotic may be the key target, but alternative or additional functions including repression of transcription through glycosylation of the C-terminal domain of RNA polymerase II are also possible.

Transgenic Primate Research Paves the Path to a Better Animal Model: Are We a Step Closer to Curing Inherited Human Genetic Disorders?

Chan, A. W.S. — Fri, 25 Sep 2009 08:13:40 PDT

While the advancement of transgenic primate models has led to a new era in modeling human conditions and has a clear impact on elucidating the mechanism of human genetic diseases, some thoughts should be considered if non-human primates are the appropriate model.

Do Substantia Nigra Dopaminergic Neurons Differentiate Between Reward and Punishment?

Frank, M. J., Surmeier, D. J. — Fri, 25 Sep 2009 08:13:40 PDT

The activity of dopaminergic neurons are thought to be increased by stimuli that predict reward and decreased by stimuli that predict aversive outcomes. Recent work by Matsumoto and Hikosaka challenges this model by asserting that stimuli associated with either rewarding or aversive outcomes increase the activity of dopaminergic neurons in the substantia nigra pars compacta.

CCR3: Shedding New Light on a Dark Problem?

Mason, A. B., Hoh, J. — Fri, 25 Sep 2009 08:13:40 PDT

A recent work by Ambati et al. represents a bold step towards a more effective diagnosis and treatment of age-related macular degeneration, with the new evidence showing that CCR3, a chemokine receptor, is an early marker of and potential therapeutic target for choroidal neovascularization development. In the wake of such a novel and significant finding, additional illumination to confirm and consolidate the promise shown by CCR3 will soon follow.

How Diverse--CD4 Effector T Cells and their Functions

Wan, Y. Y., Flavell, R. A. — Fri, 25 Sep 2009 08:13:40 PDT

CD4 effector T cells, also called helper T (Th) cells, are the functional cells for executing immune functions. Balanced immune responses can only be achieved by proper regulation of the differentiation and function of Th cells. Dysregulated Th cell function often leads to inefficient clearance of pathogens and causes inflammatory diseases and autoimmunity. Since the establishment of the Th1–Th2 dogma in the 1980s, different lineages of effector T cells have been identified that not only promote but also suppress immune responses. Through years of collective efforts, much information was gained on the function and regulation of different subsets of Th cells. In this review, we attempt to sample the essence of what has been learnt in this field over the past two decades. We will discuss the classification and immunological functions of effector T cells, the determinants for effector T cell differentiation, as well as the relationship between different lineages of effector T cells.

PAMAM Nanoparticles Promote Acute Lung Injury by Inducing Autophagic Cell Death through the Akt-TSC2-mTOR Signaling Pathway

Fri, 25 Sep 2009 08:13:40 PDT

Nanotechnology is an important and emerging industry with a projected annual market of around one trillion US dollars by 2011–2015. Concerns about the toxicity of nanomaterials in humans, however, have recently been raised. Although studies of nanoparticle toxicity have focused on lung disease the molecular link between nanoparticle exposure and lung injury remained unclear. In this report, we show that cationic Starburst polyamidoamine dendrimer (PAMAM), a class of nanomaterials that are being widely developed for clinical applications can induce acute lung injury in vivo. PAMAM triggers autophagic cell death by deregulating the Akt-TSC2-mTOR signaling pathway. The autophagy inhibitor 3-methyladenine rescued PAMAM dendrimer-induced cell death and ameliorated acute lung injury caused by PAMAM in mice. Our data provide a molecular explanation for nanoparticle-induced lung injury, and suggest potential remedies to address the growing concerns of nanotechnology safety.

Generation of Pig Induced Pluripotent Stem Cells with a Drug-Inducible System

Fri, 25 Sep 2009 08:13:40 PDT

Domesticated ungulate pluripotent embryonic stem (ES) cell lines would be useful for generating precise gene-modified animals. To date, many efforts have been made to establish domesticated ungulate pluripotent ES cells from early embryos without success. Here, we report the generation of porcine-induced pluripotent stem (iPS) cells using drug-inducible expression of defined factors. We showed that porcine iPS cells expressed alkaline phosphatase, SSEA3, SSEA4, Tra-1-60, Tra-1-81, Oct3/4, Nanog, Sox2, Rex1 and CDH1. Pig iPS cells expressed high levels of telomerase activity and showed normal karyotypes. These cells could differentiate into cell types of all three germ layers in vitro and in teratomas. Our study reveals properties of porcine pluripotent stem cells that may facilitate the eventual establishment of porcine ES cells. Moreover, the porcine iPS cells produced may be directly useful for the generation of precise gene-modified pigs.