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2006

Genetics and Genomics

University of Massachusetts Medical School

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Articles 1 - 17 of 17

Full-Text Articles in Life Sciences

Activated Checkpoint Kinase 2 Provides A Survival Signal For Tumor Cells, Jagadish C. Ghosh, Takehiko Dohi, Christopher M. Raskett, Timothy F. Kowalik, Dario C. Altieri Dec 2006

Activated Checkpoint Kinase 2 Provides A Survival Signal For Tumor Cells, Jagadish C. Ghosh, Takehiko Dohi, Christopher M. Raskett, Timothy F. Kowalik, Dario C. Altieri

Open Access Articles

Tumor cells often become resistant to DNA damage-based therapy; however, the underlying mechanisms are not yet understood. Here, we show that tumor cells exposed to DNA damage counteract cell death by releasing the antiapoptotic protein, survivin, from mitochondria. This is independent of p53, and requires activated checkpoint kinase 2 (Chk2), a putative tumor suppressor. Molecular or genetic targeting of Chk2 prevents the release of survivin from mitochondria, enhances DNA damage-induced tumor cell apoptosis, and inhibits the growth of resistant in vivo tumors. Therefore, activated Chk2 circumvents its own tumor-suppressive functions by promoting tumor cell survival. Inhibiting Chk2 in combination with ...


Structure Of The Yeast Histone H3-Asf1 Interaction: Implications For Chaperone Mechanism, Species-Specific Interactions, And Epigenetics, Andrew J. Antczak, Toshiaki Tsubota, Paul D. Kaufman, James M. Berger Dec 2006

Structure Of The Yeast Histone H3-Asf1 Interaction: Implications For Chaperone Mechanism, Species-Specific Interactions, And Epigenetics, Andrew J. Antczak, Toshiaki Tsubota, Paul D. Kaufman, James M. Berger

Program in Gene Function and Expression Publications and Presentations

BACKGROUND: The histone H3/H4 chaperone Asf1 (anti-silencing function 1) is required for the establishment and maintenance of proper chromatin structure, as well as for genome stability in eukaryotes. Asf1 participates in both DNA replication-coupled (RC) and replication-independent (RI) histone deposition reactions in vitro and interacts with complexes responsible for both pathways in vivo. Asf1 is known to directly bind histone H3, however, high-resolution structural information about the geometry of this interaction was previously unknown. RESULTS: Here we report the structure of a histone/histone chaperone interaction. We have solved the 2.2 A crystal structure of the conserved N-terminal ...


Cbfbeta Reduces Cbfbeta-Smmhc-Associated Acute Myeloid Leukemia In Mice, Susan Ann Heilman, Ya-Huei Kuo, Chantal S. Goudswaard, Peter J. Valk, Lucio H. Castilla Dec 2006

Cbfbeta Reduces Cbfbeta-Smmhc-Associated Acute Myeloid Leukemia In Mice, Susan Ann Heilman, Ya-Huei Kuo, Chantal S. Goudswaard, Peter J. Valk, Lucio H. Castilla

Open Access Articles

The gene encoding for core-binding factor beta (CBFbeta) is altered in acute myeloid leukemia samples with an inversion in chromosome 16, expressing the fusion protein CBFbeta-SMMHC. Previous studies have shown that this oncoprotein interferes with hematopoietic differentiation and proliferation and participates in leukemia development. In this study, we provide evidence that Cbfbeta modulates the oncogenic function of this fusion protein. We show that Cbfbeta plays an important role in proliferation of hematopoietic progenitors expressing Cbfbeta-SMMHC in vitro. In addition, Cbfbeta-SMMHC-mediated leukemia development is accelerated in the absence of Cbfbeta. These results indicate that the balance between Cbfbeta and Cbfbeta-SMMHC directly ...


Trefoil Family Factor 2 Is Expressed In Murine Gastric And Immune Cells And Controls Both Gastrointestinal Inflammation And Systemic Immune Responses, Evelyn A. Kurt-Jones, Lucheng Cao, Frantisek Sandor, Arlin B. Rogers, Mark T. Whary, Prashant R. Nambiar, Anna M. Cerny, Glennice N. Bowen, Jing Yan, Shigeo Takaishi, Alfred L. Chi, George W. Reed, Jeanmarie Houghton, James G. Fox, Timothy C. Wang Nov 2006

Trefoil Family Factor 2 Is Expressed In Murine Gastric And Immune Cells And Controls Both Gastrointestinal Inflammation And Systemic Immune Responses, Evelyn A. Kurt-Jones, Lucheng Cao, Frantisek Sandor, Arlin B. Rogers, Mark T. Whary, Prashant R. Nambiar, Anna M. Cerny, Glennice N. Bowen, Jing Yan, Shigeo Takaishi, Alfred L. Chi, George W. Reed, Jeanmarie Houghton, James G. Fox, Timothy C. Wang

Open Access Articles

Trefoil family factor 2 (TFF2), also known as spasmolytic peptide, is a low-molecular-weight protein that is upregulated in gastric tissues infected with Helicobacter or having other inflammatory conditions, but a precise function is yet to be elucidated. The role of TFF2 in the development of gastritis, colitis, and inflammatory cytokine responses was examined both in vivo and in vitro using wild-type and TFF2 knockout mice. TFF2 knockout and wild-type mice were infected with Helicobacter felis (H. felis) to induce gastritis. Colitis was induced in TFF2 knockout and wild-type mice by administering dextran sodium sulfate (DSS) in drinking water. Histopathology, clinical ...


Autophagy Is Activated For Cell Survival After Endoplasmic Reticulum Stress, Maiko Ogata, Shin-Ichiro Hino, Atsushi Saito, Keisuke Morikawa, Shinichi Kondo, Soshi Kanemoto, Tomohiko Murakami, Manabu Taniguchi, Ichiro Tanii, Kazuya Yoshinaga, Sadao Shiosaka, James A. Hammarback, Fumihiko Urano, Kazunori Imaizumi Oct 2006

Autophagy Is Activated For Cell Survival After Endoplasmic Reticulum Stress, Maiko Ogata, Shin-Ichiro Hino, Atsushi Saito, Keisuke Morikawa, Shinichi Kondo, Soshi Kanemoto, Tomohiko Murakami, Manabu Taniguchi, Ichiro Tanii, Kazuya Yoshinaga, Sadao Shiosaka, James A. Hammarback, Fumihiko Urano, Kazunori Imaizumi

Program in Gene Function and Expression Publications and Presentations

Eukaryotic cells deal with accumulation of unfolded proteins in the endoplasmic reticulum (ER) by the unfolded protein response, involving the induction of molecular chaperones, translational attenuation, and ER-associated degradation, to prevent cell death. Here, we found that the autophagy system is activated as a novel signaling pathway in response to ER stress. Treatment of SK-N-SH neuroblastoma cells with ER stressors markedly induced the formation of autophagosomes, which were recognized at the ultrastructural level. The formation of green fluorescent protein (GFP)-LC3-labeled structures (GFP-LC3 "dots"), representing autophagosomes, was extensively induced in cells exposed to ER stress with conversion from LC3-I to ...


Chromosome Conformation Capture Carbon Copy (5c): A Massively Parallel Solution For Mapping Interactions Between Genomic Elements, Josee Dostie, Todd A. Richmond, Ramy A. Arnaout, Rebecca R. Selzer, William L. Lee, Tracey A. Honan, Eric D. Rubio, Anton Krumm, Justin Lamb, Chad Nusbaum, Roland D. Green, Job Dekker Oct 2006

Chromosome Conformation Capture Carbon Copy (5c): A Massively Parallel Solution For Mapping Interactions Between Genomic Elements, Josee Dostie, Todd A. Richmond, Ramy A. Arnaout, Rebecca R. Selzer, William L. Lee, Tracey A. Honan, Eric D. Rubio, Anton Krumm, Justin Lamb, Chad Nusbaum, Roland D. Green, Job Dekker

Open Access Articles

Physical interactions between genetic elements located throughout the genome play important roles in gene regulation and can be identified with the Chromosome Conformation Capture (3C) methodology. 3C converts physical chromatin interactions into specific ligation products, which are quantified individually by PCR. Here we present a high-throughput 3C approach, 3C-Carbon Copy (5C), that employs microarrays or quantitative DNA sequencing using 454-technology as detection methods. We applied 5C to analyze a 400-kb region containing the human beta-globin locus and a 100-kb conserved gene desert region. We validated 5C by detection of several previously identified looping interactions in the beta-globin locus. We also ...


Probing Protein Dynamics Through Mutational And Computational Studies Of Hiv-1 Protease: A Dissertation, Jennifer E. Murzycki Sep 2006

Probing Protein Dynamics Through Mutational And Computational Studies Of Hiv-1 Protease: A Dissertation, Jennifer E. Murzycki

GSBS Dissertations and Theses

How proteins undergo conformational changes to bind a ligand is one of the most fundamental questions of protein biology. MD simulations provide a useful computational tool for studying the theoretical movements of protein in solution on nanosecond timescales. The results of these simulations can be used to guide experimental design. By correlating the theoretical models with the results of experimental studies, we can obtain a significant amount of information about protein dynamics. This study represents the application of both computational and traditional experimental techniques to study protein dynamics in HIV-1 protease. The results provide a novel mechanism for the conformational ...


Designing Sirna That Distinguish Between Genes That Differ By A Single Nucleotide, Dianne S. Schwarz, Hongliu Ding, Lori A. Kennington, Jessica T. Moore, Janell M. Schelter, Julja Burchard, Peter S. Linsley, Neil Aronin, Zuoshang Xu, Phillip D. Zamore Sep 2006

Designing Sirna That Distinguish Between Genes That Differ By A Single Nucleotide, Dianne S. Schwarz, Hongliu Ding, Lori A. Kennington, Jessica T. Moore, Janell M. Schelter, Julja Burchard, Peter S. Linsley, Neil Aronin, Zuoshang Xu, Phillip D. Zamore

GSBS Student Publications

Small interfering RNAs (siRNAs), the guides that direct RNA interference (RNAi), provide a powerful tool to reduce the expression of a single gene in human cells. Ideally, dominant, gain-of-function human diseases could be treated using siRNAs that specifically silence the mutant disease allele, while leaving expression of the wild-type allele unperturbed. Previous reports suggest that siRNAs can be designed with single nucleotide specificity, but no rational basis for the design of siRNAs with single nucleotide discrimination has been proposed. We systematically identified siRNAs that discriminate between the wild-type and mutant alleles of two disease genes: the human Cu, Zn superoxide ...


From Imaging To Understanding: Frontiers In Live Cell Imaging, Bethesda, Md, April 19-21, 2006, Yu-Li Wang, Klaus M. Hahn, Robert F. Murphy, Alan F. Horwitz Aug 2006

From Imaging To Understanding: Frontiers In Live Cell Imaging, Bethesda, Md, April 19-21, 2006, Yu-Li Wang, Klaus M. Hahn, Robert F. Murphy, Alan F. Horwitz

Open Access Articles

No abstract provided.


The Active Fmr1 Promoter Is Associated With A Large Domain Of Altered Chromatin Conformation With Embedded Local Histone Modifications, Nele Gheldof, Tomoko M. Tabuchi, Job Dekker Aug 2006

The Active Fmr1 Promoter Is Associated With A Large Domain Of Altered Chromatin Conformation With Embedded Local Histone Modifications, Nele Gheldof, Tomoko M. Tabuchi, Job Dekker

Open Access Articles

We have analyzed the effects of gene activation on chromatin conformation throughout an approximately 170-kb region comprising the human fragile X locus, which includes a single expressed gene, FMR1 (fragile X mental retardation 1). We have applied three approaches: (i) chromosome conformation capture, which assesses relative interaction frequencies of chromatin segments; (ii) an extension of this approach that identifies domains whose conformation differs from the average, which we developed and named chromosome conformation profiling; and (iii) ChIP analysis of histone modifications. We find that, in normal cells where FMR1 is active, the FMR1 promoter is at the center of a ...


Linkage Analysis Of Longitudinal Data And Design Consideration, Heping Zhang, Xiaoyun Zhong Jun 2006

Linkage Analysis Of Longitudinal Data And Design Consideration, Heping Zhang, Xiaoyun Zhong

Open Access Articles

BACKGROUND: Statistical methods have been proposed recently to analyze longitudinal data in genetic studies. So far, little attention has been paid to examine the relationship among key factors in genetic longitudinal studies including power, the number of families or sibships, and the number of repeated measures per individual subjects.

RESULTS: We proposed a variance component model that extends classic variance component models for a single quantitative trait to mapping longitudinal traits. Our model includes covariate effects and allows genetic effects to vary over time. Using our proposed model, we examined the power, pedigree structures, and sample size through simulation experiments ...


Epigenetic Telomere Protection By Drosophila Dna Damage Response Pathways, Sarah R. Oikemus, Joana Queiroz-Machado, Kuanju Lai, Nadine Schultz, Claudio E. Sunkel, Michael H. Brodsky May 2006

Epigenetic Telomere Protection By Drosophila Dna Damage Response Pathways, Sarah R. Oikemus, Joana Queiroz-Machado, Kuanju Lai, Nadine Schultz, Claudio E. Sunkel, Michael H. Brodsky

GSBS Student Publications

Analysis of terminal deletion chromosomes indicates that a sequence-independent mechanism regulates protection of Drosophila telomeres. Mutations in Drosophila DNA damage response genes such as atm/tefu, mre11, or rad50 disrupt telomere protection and localization of the telomere-associated proteins HP1 and HOAP, suggesting that recognition of chromosome ends contributes to telomere protection. However, the partial telomere protection phenotype of these mutations limits the ability to test if they act in the epigenetic telomere protection mechanism. We examined the roles of the Drosophila atm and atr-atrip DNA damage response pathways and the nbs homolog in DNA damage responses and telomere protection. As ...


Drosophila Melanogaster Scramblases Modulate Synaptic Transmission, Usha Acharya, Michael Beth Edwards, Ramon A. Jorquera, Hugo Silva, Kunio Nagashima, Pedro Labarca, Jairaj K. Acharya Apr 2006

Drosophila Melanogaster Scramblases Modulate Synaptic Transmission, Usha Acharya, Michael Beth Edwards, Ramon A. Jorquera, Hugo Silva, Kunio Nagashima, Pedro Labarca, Jairaj K. Acharya

Program in Gene Function and Expression Publications and Presentations

Scramblases are a family of single-pass plasma membrane proteins, identified by their purported ability to scramble phospholipids across the two layers of plasma membrane isolated from platelets and red blood cells. However, their true in vivo role has yet to be elucidated. We report the generation and isolation of null mutants of two Scramblases identified in Drosophila melanogaster. We demonstrate that flies lacking either or both of these Scramblases are not compromised in vivo in processes requiring scrambling of phospholipids. Instead, we show that D. melanogaster lacking both Scramblases have more vesicles and display enhanced recruitment from a reserve pool ...


Mitosis-Independent Survivin Gene Expression In Vivo And Regulation By P53, Fang Xia, Dario C. Altieri Apr 2006

Mitosis-Independent Survivin Gene Expression In Vivo And Regulation By P53, Fang Xia, Dario C. Altieri

Open Access Articles

Survivin is an essential mitotic gene, and this has been speculated to reflect its primary function in development and cancer. Here, we generated a knock-in transgenic mouse (SVVp-GFP) in which a green fluorescent protein (GFP) reporter gene was placed under the control of the survivin promoter that regulates transcription at mitosis. The expression of endogenous survivin was widespread in mouse tissues during development and shortly after birth. In contrast, GFP reactivity was undetectable in transgenic mouse embryos, and was largely limited postnatally to mitotic cells in the testes. Double transgenic mice generated in the tumor-prone Min/+ background exhibited intestinal adenomas ...


Counter-Selectable Marker For Bacterial-Based Interaction Trap Systems, Xiangdong Meng, Robin M. Smith, Astrid V. Giesecke, J. Keith Joung, Scot A. Wolfe Mar 2006

Counter-Selectable Marker For Bacterial-Based Interaction Trap Systems, Xiangdong Meng, Robin M. Smith, Astrid V. Giesecke, J. Keith Joung, Scot A. Wolfe

Program in Gene Function and Expression Publications and Presentations

Counter-selectable markers can be used in two-hybrid systems to search libraries for a protein or compound that interferes with a macromolecular interaction or to identify macromolecules from a population that cannot mediate a particular interaction. In this report, we describe the adaptation of the yeast URA3/5-FOA counter-selection system for use in bacterial interaction trap experiments. Two different URA3 reporter systems were developed that allow robust counter-selection: (i) a single copy F' episome reporter and (ii) a co-cistronic HIS3-URA3 reporter vector. The HIS3-URA3 reporter can be used for either positive or negative selections in appropriate bacterial strains. These reagents extend ...


Towards The Visualization Of Genome Activity At Nanoscale Dimensions, Joan C. Ritland Politz Mar 2006

Towards The Visualization Of Genome Activity At Nanoscale Dimensions, Joan C. Ritland Politz

Open Access Articles

No abstract provided.


Biochemistry And Molecular Biology, Albertha J. M. Walhout, Simon J. Boulton Feb 2006

Biochemistry And Molecular Biology, Albertha J. M. Walhout, Simon J. Boulton

Program in Gene Function and Expression Publications and Presentations

Several forward and reverse proteomic approaches are available that can be used to identify interaction partners for a protein of interest. Here we provide methods for identifying interacting partners by the yeast two-hybrid system (a reverse proteomic method) and by tandem immuno-affinity purification of protein complexes combined with mass spectrometry (a forward proteomic method).