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New study by Brugge lab uncovers apoptotic vulnerabilities in ovarian cancer - Sep 22, 2017

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High-grade serous ovarian cancers (HGS-OvCa) frequently develop chemotherapy resistance; therefore, identification of novel therapies for the treatment of chemotherapy-resistant tumors remains an unmet need. In a recent study published in Nature Communications, the Brugge lab carried out a systematic proteomic profiling analysis of responses to PI3K/mTOR inhibition in 14 HGS-OvCa patient-derived xenografts (PDX) to identify vulnerabilities of chemotherapy-resistant ovarian cancer.  Findings from these studies showed that PI3K/mTOR inhibition strongly promotes apoptotic priming which sensitizes cells to inhibition of BCL2 family anti-apoptotic proteins. Combined inhibition of the PI3K/AKT/mTOR axis and BCL-2/BCL-Xinduces effective tumor cell death in vitro and in orthotopic mouse xenografts in vivo. By performing an in-depth analysis of the BCL-2 family of apoptotic regulators using selective inhibitors and computational modeling, the Brugge lab identified BIM, BCL-XL and MCL-1 as critical players and biomarkers in ovarian cancer cell survival. This study presents a novel systematic approach to comprehensively investigate apoptotic priming mechanisms and identify cell death vulnerabilities in HGS-OvCa.
 

Bob Farese announced as a 2018 Laureate Award winner by the Endocrine Society - Sep 14, 2017

Bob Farese

Bob Farese has been selected as one of 14 leaders in the endocrinology field to receive a prestigious 2018 Laureate Award from the Endocrine Society. Established in 1944, these awards recognize the highest achievements in the field of endocrinology, including groundbreaking resesarch and innovations in clinical care. Bob was awarded the Roy O. Greep Award for Outstanding Research for his seminal contributions to the understanding of cellular lipid metabolism. His work has shown how alterations in lipid synthesis and storage contribute to the pathogenesis of human diseases, in particular type 2 diabetes, and has suggested new targets for therapy. Bob also pioneered the cell biology of lipid droplets, the cellular organelle responsible for storing triglycerides and metabolic energy, including identifying hundreds of genes that govern lipid storage in cells. To learn more, please click here.

Liao lab uncovers the structural basis for LPS transport by ABC transporter MsbA - Sep 08, 2017

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Lipopolysaccharide (LPS, also known as endotoxin) in Gram-negative bacteria is critical for the bacterial survival and their resistance to antibiotics. As a critical step of LPS biosynthesis, newly produced LPS in the cytoplasmic leaflet of the inner membrane is flipped to the periplasmic leaflet by MsbA, an ATP-binding cassette transporter. In a recent study published in Nature on September 6, the Liao lab use single particle cryo-EM to obtain high-resolution snapshots of MsbA at different functional states. This study uncovers the structural basis for LPS transport, and paves the way for structural characterization of many other lipid flippases.

Finley lab discovers how red blood cells remodel during terminal differentiation - Aug 24, 2017

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The Finley lab, in a recent publication in Science, found that a mutation in the murine Ube2o gene, which encodes an ubiquitin-conjugating enzyme induced during erythropoiesis, results in anemia. Proteomic analysis suggested that UBE2O is a broad-spectrum ubiquitinating enzyme that remodels the erythroid proteome. You can read more about this research in an article here on the HMS news webpage.

Depolymerase mechanism for a length-dependent microtubule regulator defined by Pellman lab - Aug 23, 2017

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Proper establishment of the size of intracellular microtubule-based structures, the mitotic spindle or the cilia, is key for their cellular function. One class of mechanisms mediating size control of these intracellular structures utilizes molecular motors as “measuring devices”.  Kinesin-8 motors have a conserved role in regulating the size of microtubule structures, using length-dependent accumulation at the plus-end to preferentially disassemble long microtubules. Despite extensive study, the kinesin-8 depolymerase mechanism has been debated. In a paper recently published in Developmental Cell, the Pellman lab (with first author Hugo Arellano-Santoyo) defined a tubulin curvature-sensing mechanism for Kip3/kinesin-8 depolymerization. On the straight tubulin of the microtubule lattice, Kip3 behaves like conventional motile kinesin, using ATP for processive stepping, as assayed by single molecule imaging. Upon reaching the curved tubulin of the microtubule plus-end, Kip3 undergoes a switch: Its ATPase activity is suppressed when it binds tightly to the curved conformation of tubulin. This prolongs plus-end binding, stabilizes protofilament curvature, and ultimately promotes microtubule disassembly. This tubulin-binding switch has allowed the co-existence of motility and depolymerase activity in Kip3/kinesin-8s, which is central to their ability to regulate the length of cellular microtubule structures. These findings also illustrate how small scale tuning of binding affinities and rate constants for an enzyme can generate strikingly divergent macroscopic properties.

Farese and Walther lab discovers triglyceride synthesis enzyme DGAT1 protects adipocytes from lipid induced ER stress during lipolysis - Aug 10, 2017

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Triglyceride (TG) storage in adipose tissue provides the major reservoir for metabolic energy in mammals. During lipolysis, fatty acids (FAs) are hydrolyzed from adipocyte TG stores and transported to other tissues for fuel. For unclear reasons, a large portion of hydrolyzed FAs in adipocytes is re-esterified to TGs in a “futile”, ATP-consuming, energy dissipating cycle. The Farese & Walther lab's recent publication in Cell Metabolism shows that FA re-esterification during adipocyte lipolysis is mediated by DGAT1, an ER-localized DGAT enzyme. Surprisingly, this re-esterification cycle does not preserve TG mass, but instead functions to protect the ER from lipotoxic stress and related consequences, such as adipose tissue inflammation. These results reveal an important role for DGAT activity and TG synthesis generally in averting ER stress and lipotoxicity, with specifically DGAT1 performing this function during stimulated lipolysis in adipocytes.

Recent Faculty Promotion: Adrian Salic - Jul 21, 2017

Adrian Salic

Congratulations to Adrian Salic on his promotion to Professor of Cell Biology!

Adrian uses biochemistry, cell, and chemical biology to elucidate how vertebrate cells send and respond to Hedgehog signals. Two key aspects his lab is currently investigating are the activation of the secreted Hedgehog protein and the regulated proteolysis of Gli, the transcriptional effector of the Hedghog pathway. 

Rapoport and Liao labs determine the cryo-EM structure of the ERAD Hrd1/Hrd3 complex - Jul 19, 2017

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A conserved pathway called “endoplasmic reticulum associated protein degradation (ERAD) is responsible for the disposal of misfolded ER proteins. Previous work from the Rapoport lab indicated that the multi-spanning ubiquitin ligase Hrd1 is a key component of ERAD; Hrd1 allows misfolded luminal and membrane proteins to move from the ER into the cytosol. However, it remained unclear whether Hrd1 forms a protein-conducting channel. In a paper recently published in Nature, the Rapoport and Liao labs teamed up to determine a single particle cryo-EM structure of Hrd1 together with its luminal binding partner Hrd3. The Hrd1/Hrd3 complex structure at ~4 Å shows that Hrd1 forms a dimer inside the membrane with two Hrd3 molecules forming a luminal arch above the dimer. Each Hrd1 molecule has a large hydrophilic cavity extending from the cytosol almost to the ER lumen. A trans-membrane segment of the other Hrd1 molecule forms a lateral seal of the cavity. Both the cavity and the lateral gate are reminiscent of other protein-conducting conduits, such as the Sec61/SecY channel or the YidC protein, which allow proteins to move in the other direction, i.e. from the cytosol into the membrane. These results indicate that the thinning of the lipid bilayer may be a general principle employed by protein-conducting conduits to lower the energetic barrier for moving hydrophobic segments in or out of the membrane.

Liao lab discovers key steps in CRISPR’s mechanism of action - Jul 06, 2017

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Scientists in the Liao lab and Cornell University have produced near-atomic resolution snapshots of CRISPR that reveal key steps in its mechanism of action. The findings, published in Cell on June 29, provide the structural data necessary for efforts to improve the efficiency and accuracy of CRISPR for biomedical applications. You can read more at HMS News, Science Newsline, Phys.org, and Science Daily

New study by Reed lab reveals how RNA splicing errors may cause the development of ALS and a specific form of dementia - Jun 13, 2017

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The most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) may stem from errors in RNA splicing, an intermediary and critical step for translating genetic instructions into functional proteins. In a recent study published in Cell Reports on June 13, the Reed lab shows that toxic peptides produced by mutation of the C9ORF72 gene can prevent accurate assembly of the spliceosome—the molecular machine responsible for RNA splicing.

For more information, please read the article here.

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