Category Archives: Pathways

Recommended Readings: Alexander Varshavsky, Ph.D.

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Friday Lecture Series

William H. Stein Memorial Lecture

Recent Discoveries about the Ubiquitin System and the N-end Rule Pathway

Alexander Varshavsky, Ph.D.,

Howard and Gwen Laurie Smits Professor of Cell Biology,

California Institute of Technology

April 26, 2012

3:45 p.m.-5:00 p.m. (Refreshments, 3:15 p.m., Abby Lounge)

Caspary Auditorium

Recommended Readings

Graciet, E., Walter, F., Maoiléidigh, D. Ó., Pollmann, S., Meyerowitz, E. M., Varshavsky, A., & Wellmer, F. (2009). The N-end rule pathway controls multiple functions during arabidopsis shoot and leaf development. Proceedings of the National Academy of Sciences of the United States of America, 106(32), 13618-13623

Hwang, C. -., Shemorry, A., Auerbach, D., & Varshavsky, A. (2010). The N-end rule pathway is mediated by a complex of the RING-type Ubr1 and HECT-type Ufd4 ubiquitin ligases. Nature Cell Biology, 12(12), 1177-1185

Hwang, C. -., Shemorry, A., & Varshavsky, A. (2010). N-terminal acetylation of cellular proteins creates specific degradation signals. Science, 327(5968), 973-977

Hwang, C. -., Shemorry, A., & Varshavsky, A. (2009). Two proteolytic pathways regulate DNA repair by cotargeting the Mgt1 alkylguanine transferase. Proceedings of the National Academy of Sciences of the United States of America, 106(7), 2142-2147

Varshavsky, A. (2006). The early history of the ubiquitin field. Protein Science, 15(3), 647-654

Varshavsky, A. (2011). The N-end rule pathway and regulation by proteolysis. Protein Science, 20(8), 1298-1345

Xia, Z., Webster, A., Du, F., Piatkov, K., Ghislain, M., & Varshavsky, A. (2008). Substrate-binding sites of UBR1, the ubiquitin ligase of the N-end rule pathway. Journal of Biological Chemistry, 283(35), 24011-24028

 

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Recommended Readings: Maurice Swanson, Ph.D.

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Friday Lecture Series

RNA-mediated Pathways to Disease

Maurice Swanson, Ph.D., associate director, Center for NeuroGenetics,

and professor of molecular genetics and microbiology,

University of Florida College of Medicine

 February 15, 2012

3:45 p.m.-5:00 p.m. (Refreshments, 3:15 p.m., Abby Lounge)

Caspary Auditorium

Recommended Readings

Daughters, R. S., Tuttle, D. L., Gao, W., Ikeda, Y., Moseley, M. L., Ebner, T. J., . . . Ranum, L. P. W. (2009). RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genetics, 5(8)

Ho, T. H., Savkur, R. S., Poulos, M. G., Mancini, M. A., Swanson, M. S., & Cooper, T. A. (2005). Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy. Journal of Cell Science, 118(13), 2923-2933

Kanadia, R. N., Shin, J., Yuan, Y., Beattie, S. G., Wheeler, T. M., Thornton, C. A., & Swanson, M. S. (2006). Reversal of RNA missplicing and myotonia after muscleblind overexpression in a mouse poly(CUG) model for myotonic dystrophy. Proceedings of the National Academy of Sciences of the United States of America, 103(31), 11748-11753

Osborne, R. J., Lin, X., Welle, S., Sobczak, K., O’Rourke, J. R., Swanson, M. S., & Thornton, C. A. (2009). Transcriptional and post-transcriptional impact of toxic RNA in myotonic dystrophy. Human Molecular Genetics, 18(8), 1471-1481

Shin, J., Charizanis, K., & Swanson, M. S. (2009). Pathogenic RNAs in microsatellite expansion disease. Neuroscience Letters, 466(2), 99-102

Yuan, Y., Compton, S. A., Sobczak, K., Stenberg, M. G., Thornton, C. A., Griffith, J. D., & Swanson, M. S. (2007). Muscleblind-like 1 interacts with RNA hairpins in splicing target and pathogenic RNAs. Nucleic Acids Research, 35(16), 5474-5486

 

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Recommended Readings: Jeffrey V. Ravetch, Ph. D.

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Friday Lecture Series

The Paradox of Immunity

Jeffrey V. Ravetch, M.D., Ph.D., Theresa and Eugene M. Lang Professor and head,

Leonard Wagner Laboratory of Molecular Genetics and Immunology,

The Rockefeller University

March 9, 2012

3:45 p.m.-5:00 p.m. (Refreshments, 3:15 p.m., Abby Lounge)

Caspary Auditorium

 

Recommended Readings:

Anthony, R. M., F. Nimmerjahn, D. J. Ashline, V. N. Reinhold, J. C. Paulson, and J. V. Ravetch. 2008. Recapitulation of IVIG anti-inflammatory activity with a recombinant IgG fc. Science 320, (5874): 373-376

Durandy, A., S. V. Kaveri, T. W. Kuijpers, M. Basta, S. Miescher, J. V. Ravetch, and R. Rieben. 2009. Intravenous immunoglobulins-understanding properties and mechanisms. Clinical and experimental immunology 158, (SUPPL. 1): 2-13

Nimmerjahn, F., and J. V. Ravetch. 2010. Antibody-mediated modulation of immune responses. Immunological reviews 236, (1): 265-275

Ravetch, J. 2010. In vivo veritas: The surprising roles of fc receptors in immunity. Nature immunology 11, (3): 183-185

Sazinsky, S. L., R. G. Ott, N. W. Silver, B. Tidor, J. V. Ravetch, and K. D. Wittrup. 2008. Aglycosylated immunoglobulin G1 variants productively engage activating fc receptors. Proceedings of the National Academy of Sciences of the United States of America 105, (51): 20167-20172

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Recommended Readings: Victor Ambros, Ph.D.

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Friday Lecture Series


microRNA Pathways in Animal Development

Joshua Lederberg Distinguished Lectureship in Molecular Genetics


Victor Ambros, Ph.D., Silverman Professor of Natural Science, co-director,

RNA Therapeutics Institute,

University of Massachusetts Medical School

February 3, 2012

3:45 p.m.-5:00 p.m. (Refreshments, 3:15 p.m., Abby Lounge)

Caspary Auditorium

Recommended Readings:

Ambros, V. 2010. MicroRNAs: Genetically sensitized worms reveal new secrets. Current Biology 20, (14): R598-R600

Hammell, C. M., X. Karp, and V. Ambros. 2009. A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in caenorhabditis elegans. Proceedings of the National Academy of Sciences of the United States of America 106, (44): 18668-18673

Hammell, C. M., I. Lubin, P. R. Boag, T. K. Blackwell, and V. Ambros. 2009. Nhl-2 modulates MicroRNA activity in caenorhabditis elegans. Cell 136, (5): 926-938

Hammell, M., D. Long, L. Zhang, A. Lee, C. S. Carmack, M. Han, Y. Ding, and V. Ambros. 2008. mirWIP: MicroRNA target prediction based on microRNA-containing ribonucleoprotein-enriched transcripts. Nature Methods 5, (9): 813-819

Miska, E. A., E. Alvarez-Saavedra, A. L. Abbott, N. C. Lau, A. B. Hellman, S. M. McGonagle, D. P. Bartel, V. R. Ambros, and H. R. Horvitz. 2007. Most caenorhabditis elegans microRNAs are individually not essential for development or viability. PLoS Genetics 3, (12): 2395-2403

Sokol, N. S., P. Xu, Y. -N Jan, and V. Ambros. 2008. Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis. Genes and Development 22, (12): 1591-1596

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How Cells Detect Tissue Damage And Proceed With Repairs

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A  Wellcome Trust-funded study, led by biochemists at the University of Bristol, examined the signalling process in damaged tissue cells and identified the cellular mechanisms responsible for activating effective repair. 

In healthy adults the majority of tissue cells lie dormant unless challenged by wounding, at which point they sense a change in the molecular environment. Plasma leaking from damaged blood vessels and causes fibroblast cells to migrate into the damaged tissue, contract the wound, and plug the gap by depositing a substance such as collagen, which provides the structural support.   Read more about this research in Developmental Cell.

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Cancer Drug Candidate Leads to Proteomics Method

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Scientists at Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical have devised an affinity capture-based proteomics technique that could be used to identify and map dysregulated protein pathways in a number of different cancers.

The technique, which was detailed in a paper published Nature Chemical Biology, relies on the inhibitor PU-H71 – a small molecule that selectively binds tumor-enriched Hsp90 proteins, enabling pulldown of Hsp90-bound oncogenic client proteins. According to MSK researcher Gabriela Chiosis ― one of the developers of the method ― measurement of these captured proteins combined with bioinformatic analysis could provide a better understanding of tumor biology.

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Proton Pump Functions By Protein Bound Transient Chain of Water Molecules

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Researchers from have succeeded in providing evidence that a protein is capable of creating a water molecule chain for a few milliseconds for the directed proton transfer. The combination of vibrational spectroscopy and biomolecular simulations enabled the elucidation of the proton pump mechanism of a cell-membrane protein in atomic detail. The researchers demonstrated that protein-bound water molecules play a decisive role in the function.  Details of these revelations published in PNAS online.

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Expanding the horizon of chemotherapeutic targets: From MDM2 to MDMX (MDM4)

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Antonio Macchiarulo, Nicola Giacchè, Andrea Carotti, Fabiola Moretti and Roberto Pellicciari

DOI: 10.1039/C0MD00238K

Alterations of p53 signalling pathway is the most frequent event in human cancers. About 50% of these, albeit showing wild-type p53, have flaws in the control mechanisms of p53 levels and activity. MDM2 and MDMX (MDM4) are the main negative regulators of p53. The relevance of MDM2 on the regulation of p53 levels and activity has fostered the development of strategies aimed at restoring p53 functions by blocking the physical interaction between MDM2 and p53. As a consequence, a number of different small molecules and peptidomimetics have been disclosed in the last decade as inhibitors of MDM2/p53 interaction. Recent studies, however, have thrust MDMX into the limelight as an additional chemotherapeutic target, suggesting the presence of a more complex relationship between MDM2, MDMX and p53. In this review article, we report key aspects of MDMX-mediated regulation of p53, recent advances in the structural characterization of the protein, and the progress made so far in the medicinal chemistry of MDMX ligands.

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Recommended Readings: Peter Vogt, Ph. D.

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Friday Lecture Series

Cancer Biology Lecture

Oncogenic Signaling in the PI3K Pathway

Peter Vogt, Ph.D., professor, department of molecular and experimental medicine,

The Scripps Research Institute

April 29, 2011

3:45 p.m.-5:00 p.m. (Refreshments, 3:15 p.m., Abby Lounge)

Caspary Auditorium

Bader, A. G., S. Kang, and P. K. Vogt. 2006. Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proceedings of the National Academy of Sciences of the United States of America 103, (5): 1475-1479

Bader, A. G., S. Kang, L. Zhao, and P. K. Vogt. 2005. Oncogenic PI3K deregulates transcription and translation. Nature Reviews Cancer 5, (12): 921-929

Vogt, P. K., M. Gymnopoulos, and J. R. Hart. 2009. PI 3-kinase and cancer: Changing accents. Current Opinion in Genetics and Development 19, (1): 12-17

Vogt, P. K., S. Kang, M. -A Elsliger, and M. Gymnopoulos. 2007. Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends in biochemical sciences 32, (7): 342-349

Zhao, L., and P. K. Vogt. 2008. Class I PI3K in oncogenic cellular transformation. Oncogene 27, (41): 5486-5496

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Master Control Switch for Breast Cancer Oncogene Discovered

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Scientists have discovered an accomplice in breast cancer — a master control switch with the power to set off a cascade of reactions orchestrated by an oncogene named Wnt1. This executive molecule and its modus operandi are reported in back-to-back papers featured on the cover of the August 15 issue of Cancer Research.

Metastasis-Associated Protein 1 Short Form Stimulates Wnt1 Pathway in Mammary Epithelial and Cancer Cells

Metastasis-Associated Protein 1 and Its Short Form Variant Stimulates Wnt1 Transcription through Promoting Its Derepression from Six3 Corepressor

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