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News - Aug 13, 2013

3D reconstruction of an ER sheet connection

The endoplasmic reticulum (ER) is a continuous membrane system consisting of the nuclear envelope and a peripheral network of membrane tubules and sheets. ER sheets often form stacks, an arrangement that is likely required to accommodate a maximum number of membrane-bound polysome for secretory protein synthesis. How sheets are connected with one another was unknown until recently. As reported in Cell, the Rapoport Lab and their collaborators used a novel automated serial thin sectioning electron microscopy technique to analyze the 3D structure of stacked ER sheets of mouse neurons and of professional secretory cells of the salivary gland. The team discovered that ER sheets are connected by a novel membrane motif consisting of continuous twisted membrane surfaces with helical edges that have left or right-handedness. A theoretical model indicates that this configuration corresponds to a minimum of elastic energy of the sheet surface and its edges. The three dimensional structure resembles a parking garage and likely allows the optimal packing of ER sheets in the restricted volume of a cell.

News - Aug 08, 2013

Accumulation of mutant p53 has been recognized as an important factor that promotes cancer progression and metastasis. Thus, strategies that promote the degradation of mutant p53 might be beneficial for the treatment of cancers. In a recent issue of Genes & Development, Vakifahmetoglu-Norberg et al. demonstrate that blocking autophagy may lead to the degradation of mutant p53 through activating chaperone mediated autophagy, a lysosomal dependent degradation mechanism. This research provides a new mechanism by which mutant p53 might be degraded and the possibility of activating chaperone mediated autophagy as a new treatment for cancers with mutant p53.

News - Jul 07, 2013

In an online PNAS article, the Spiegelman Lab reports on what happens when brown, white, and beige fat cells are exposed to a range of cold temperatures in vitro. They found that cooler temperatures can directly induce white and beige fat to activate a transcriptional program leading to thermogenesis, the generation of heat from chemical energy. Unlike thermogenesis induced by brown fat, this mechanism does not require norepinephrine, the primary chemical messenger of the sympathetic nervous system. See additional news coverage in Science and The Scientist.

News - Jun 19, 2013

Histones and histone-binding proteins play important role in activating and silencing eukaryotic genes. How binding of factors to the nucleosome may change the properties of chromatin to mediate gene activation or silencing is not understood. A recent crystal structure by Wang et al. (PNAS, 2013) of the nucleosome complexed with the BAH domain of the heterochromain protein Sir3 sheds new light on this question.

Heterochromatic gene silencing in the budding yeast S. cerevisiae requires a nucleosome binding protein, Sir3, and specific histone amino acids, in particular a conserved basic patch region spanning amino acids 16 to 20 in the N-terminal tail of histone H4.  Wang and colleagues now provide evidence that association of Sir3 with the nucleosome induces interactions between the N-terminal tail of histone H4 and nucleosomal DNA.  The Moazed Lab had previously shown that a conserved region in the N-terminus of Sir3, called the BAH domain, is a nucleosome- and histone tail-binding domain. In this paper, they show that while some histone H4 side chains are critical for binding of Sir3 to the nucleosome, two arginines (R17 and R19), which are critical for silencing in vivo, have no effect on binding of Sir3 to nucleosomes in vitro.  To understand the paradoxical requirement for these arginines in gene silencing, the authors determined the 3.1 Å resolution crystal structure of the Sir3-BAH domain in complex with the nucleosome. Consistent with their biochemical data, the structure shows that R17 and R19 point away from the BAH domain and make electrostatic contacts with phosphates of the nucleosomal DNA backbone. In contrast, other histone side chains, which are also critical for silencing, make extensive bonding interactions with the BAH domain.  These observations suggest a new role for histone tails in gene silencing and heterochromatin formation, beyond assembly platforms for recruitment of regulatory factors.

News - Jun 17, 2013

Cancer cells require the biosynthesis of structural components for biomass production. This requires a reprogramming of the metabolic pathways to ensure that nutrients such as glucose and glutamine are not completely oxidized but instead their intermediary metabolites are shunted into biosynthetic pathways. Activation of the mammalian Target of Rapamycin Complex 1 (mTORC1) has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutamine metabolism has been reported. A recent paper from the Blenis Lab (Csibi et al., Cell, 2013) showed that mTORC1 activation regulates glutamine anaplerosis by promoting the conversion of glutamine to α-ketoglutarate, a tricarboxylic acid (TCA) cycle intermediate. Csibi and colleagues found that mTORC1 promotes the activity of glutamate dehydrogenase (GDH). The authors sought to identify how this occurred and found that SIRT4, an inhibitor of GDH, was repressed by mTORC1. The molecular detail of this repression involved the mTORC1-mediated phosphorylation and proteasome-mediated degradation of CREB2, a transcription factor that binds the SIRT4 human promoter. The expression of SIRT4 mRNA was decreased in several human cancers, and its forced expression in cancer cells significantly repressed proliferation, and resulted in reduced tumor development in a TSC-xenograft model. These findings suggested that targeting glutamine metabolism might impair the growth or survival of cancer cells. Indeed, the authors found that the combined pharmacological inhibition of glucose and glutamine metabolism selectively sensitized mTORC1-active cells to undergo cell death. Altogether, these results point to a central role for mTORC1 in the regulation of glutamine metabolism and suggest that the use of glutamine metabolism inhibitors may prove efficacious in nutrient-dependent cancers with high mTORC1 signaling.

 

News - Apr 29, 2013

S. Jeong
M. Haigis

Genomic instability and altered metabolism are key features of many cancer cells. Thus, defining pathways involved in regulating DNA damage responses and cellular metabolism hold important implications for understanding normal cell growth, as well as for the development of strategies to prevent or treat cancer. A recent paper from the Haigis Lab (Jeong et al, Cancer Cell, 2013) sheds new light on understanding of how cells adapt their metabolism in response to DNA damage. Jeong and colleagues report that a mitochondria-localized sirtuin, SIRT4, is up-regulated in response to DNA-damaging agents, and coordinates repression of mitochondrial glutamine metabolism with cell arrest. Loss of SIRT4 promotes genomic instability and tumor growth in mice. Moreover, SIRT4 expression is decreased in many human cancers. These findings suggest that SIRT4 has tumor suppressive activity, and provides a new link between glutamine metabolism and genomic integrity.

News - Apr 29, 2013

S. Sale
S. Artavanis-Tsakonas

The Notch signaling pathway links the fate of one cell to that of the next door cellular neighbor.  The developmental action of Notch is pleiotropic and in general Notch activity is associated with early lineages in a very broad spectrum of tissues and organs.  Consequently the Notch receptor is expressed and controls the fate of many early precursors and indeed stem cells.  Based on this, the Artavanis-Tsakonas Lab developed a series of transgenic mice in which an inducible form of the Cre recombinase has been knocked in, respectively, the Notch 1,2,3 and 4 receptor genes, thus expressing Cre in cells  expressing each receptor paralogue (Sale et al, Nat Cell Bio, 2013).  Using these tools they have been determining cell lineages and in this study they followed cell lineages associated with Notch 2 in the mammary gland.  They thus uncovered two new epithelial lineages that which allow them to revise the classical cellular hierarchies associated with mammary development.  They thus revise current models of mammary epithelial cell hierarchy and reveal a hitherto undescribed mechanism regulating branching morphogenesis.  These results may have implications for the identification of the cell-of-origin of distinct breast cancer subtypes.

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