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Danial Lab explores the coordinate regulation of hepatic energy metabolism and gluconeogenesis by the dual-function protein BAD - Mar 25, 2014

The homeostatic balance of hepatic glucose utilization, storage and production is exquisitely controlled by hormonal signals and hepatic carbon metabolism during fed and fasted states. How the liver senses extracellular glucose to cue glucose utilization versus production is not fully understood. During short term fasting, glucose is produced by both net glycogenolysis and gluconeogenesis, whereas upon prolonged fasting, glucose is synthesized almost exclusively from gluconeogenesis. Abnormal elevation of hepatic glucose production is a chief determinant of fasting hyperglycemia in diabetes. In the February 2014 issue of Cell Metabolism, the Danial Lab reported that the physiologic balance of hepatic glycolysis and gluconeogenesis is regulated by BAD, a dual function protein with roles in apoptosis and metabolism. BAD deficiency reprograms hepatic substrate and energy metabolism towards diminished glycolysis, excess fatty acid oxidation and exaggerated glucose production that escapes suppression by insulin. The group conducted genetic and biochemical studies that revealed BAD’s suppression of gluconeogenesis is actuated by phosphorylation of its BH3 domain and subsequent activation of the glucose-phosphorylating enzyme glucokinase. They also found BAD-GK axis is required for suppression of hepatic glucose production by insulin. The physiologic relevance of these findings is evident from the ability of a BAD phospho-mimic variant to counteract unrestrained gluconeogenesis and improve glycemia in leptin resistant and high-fat diet models of diabetes and insulin resistance. These findings mark BAD as a regulator of hepatic substrate metabolism and insulin sensitivity.

Reck-Peterson Lab develops new screening methods to study intracellular transport - Feb 28, 2014

Eukaryotic cells transport macromolecules over long distances along the microtubule cytoskeleton using the molecular motors dynein and kinesin. One barrier to understanding how motors transport a vast array of cargos with spatial and temporal specificity is the lack of rapid genetic methods to identify new genes involved in the process. In the March 1 issue of Molecular Biology of the Cell, the Reck-Peterson Lab reported a microscopy-based screening method involving multiplexed genome sequencing in the model organism Aspergillus nidulans. A. nidulans, a filamentous fungus, is an ideal model to study transport because of its reliance on the microtubule cytoskeleton for growth, the ease of manipulating its genome using homologous recombination, and its well-characterized life cycle that is amenable to rapid genetic analysis. Using this new screening method, the lab discovered new alleles of motors and motor regulators. Both dynein and kinesin motors transport multiple cargos in A. nidulans. One of the major findings the lab made from studying new alleles of the dynein motor was that different dynein cargos have distinct requirements for motor speed, with some cargo (the nucleus) only requiring a dynein motor that can move at a fraction of its maximal speed, while another cargo (endosomes) requiring maximal dynein velocity. This screening method will likely pave the way for many additional discoveries about the mechanism and regulation of intracellular transport.

In the figure, nuclei distribute normally in wild-type A. nidulans hyphae (top), but not in hyphae lacking dynein (bottom). Slow-velocity dynein mutants can still distribute nuclei but not endosomes, revealing cargo-specific velocity requirements.

Puigserver Lab finds that transcription factor Yin Yang 1 in the liver protects against type 2 diabetes - Feb 06, 2014

Insulin resistance is a clinical symptom of type 2 diabetes that causes profound dysregulation of glucose and lipid metabolism. In the diabetic liver, insulin no longer suppresses glucose production via the intracellular signaling or transcriptional pathways that typically suppress gluconeogenic gene expression. However, resistance to insulin does not suppress fatty acid synthesis via the transcription factor SREBP1c, resulting in lipid accumulation and exacerbating diabetic symptoms. In a new article in Molecular Endocrinology, the Puigserver Lab shows that by binding to target promoters, the transcription factor Yin Yang 1 (YY1) represses expression of genes encoding enzymes for glucose and fatty acid synthesis. At the same time, YY1 activates expression of genes encoding fatty acid oxidation enzymes. As a consequence, decreased genetic dosage of YY1 in mouse liver leads to diabetic-like symptoms such as hyperglycemia, dyslipidemia, hepatic lipid accumulation, and insulin resistance. This phenotype mimics diabetic symptoms and makes targeting YY1 an attractive approach for treating insulin-resistant diabetes.

Blenis Lab reveals how estrogen signaling may worsen LAM, a destructive lung disease found only in women - Jan 15, 2014

Lymphangioleiomyomatosis (LAM) is a destructive lung disease specific to women and is associated with the metastasis of Tuberin (TSC2)-null cells with hyperactive mTORC1 (mammalian target of rapamycin complex 1) activity. Clinical trials with the mTORC1 inhibitor rapamycin have revealed partial efficacy but are not curative. Pregnancy appears to exacerbate LAM, suggesting that estrogen (E2) may play a role in the unique features of LAM. As reported in PNAS, the Blenis Lab uses a LAM patient-derived cell line (bearing bi-allelic TSC2 inactivation) to demonstrate that E2 stimulates a robust and biphasic activation of extracellular signal-regulated kinase 2 (ERK2) and transcription of the epithelial-to-mesenchymal transition (EMT)-associated late response gene Fra1. In a carefully orchestrated collaboration, activated mTORC1/S6K1 signaling enhances the translation efficiency of Fra1 mRNA transcribed by the E2-ERK2 pathway, through S6K1-dependent eukaryotic translation initiation factor 4B (eIF4B) phosphorylation. This finding indicates that targeting the E2-ERK pathway in combination with the mTORC1 pathway may be an effective combination therapy for LAM. 

Parallel Adaptor Capture: a new proteomics approach developed by the Harper Lab - Oct 02, 2013

Modular Cullin-RING E3 ubiquitin ligases (CRLs) use substrate binding adaptor proteins to specify target ubiquitylation. Many of the ~200 human CRL adaptor proteins remain poorly studied due to a shortage of efficient methods to identify biologically relevant substrates. As reported in Molecular Cell, the Harper Lab has developed Parallel Adaptor Capture (PAC) proteomics as a new approach for the identification of CRL substrates.  They used the method to systematically identify candidate targets for the leucine-rich repeat family of F-box proteins (FBXLs) that function with SKP1-CUL1-F-box protein (SCF) E3s. This led to the identification of dozens on candidate substrates across the FBXL family. In validation experiments, they identified the unstudied F-box protein FBXL17 as a regulator of the NFR2 oxidative stress pathway, and demonstrated that FBXL17 controls the transcription of the NRF2 target HMOX1 via turnover of the transcriptional repressor BACH1 in the absence or presence of extrinsic oxidative stress. This work identifies a role for SCFFBXL17 in controlling the threshold for NRF2-dependent gene activation and provides a framework for elucidating the functions of CRL adaptor proteins.

Rapoport Lab unveils how endoplasmic reticulum stacks are connected - 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.

Yuan Lab finds that blocking macroautophagy can promote mutant p53 degradation - 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.

Spiegelman Lab discovers that some fat cells can directly sense cold temperatures and activate heat generation - 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.