Biochemistry, Biophysics, and Structural Biology Commons^™

Small-Molecule Inhibition Of Brdt For Male Contraception., Martin M. Matzuk, Michael R. Mckeown, Panagis Filippakopoulos, Qinglei Li, Lang Ma, Julio E. Agno, Madeline E. Lemieux, Sarah Picaud, Richard M. Yu, Jun Qi, Stefan Knapp, James E. Bradner

Biochemistry and Molecular Medicine Faculty Publications

A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate …

Hydrogen Peroxide Alters Splicing Of Soluble Guanylyl Cyclase And Selectively Modulates Expression Of Splicing Regulators In Human Cancer Cells, Gilbert J. Cote, Wen Zhu, Anthony Thomas, Emil Martin, Ferid Murad, Iraida G. Sharina

Biochemistry and Molecular Medicine Faculty Publications

Background

Soluble guanylyl cyclase (sGC) plays a central role in nitric oxide (NO)-mediated signal transduction in the cardiovascular, nervous and gastrointestinal systems. Alternative RNA splicing has emerged as a potential mechanism to modulate sGC expression and activity. C-α1 sGC is an alternative splice form that is resistant to oxidation-induced protein degradation and demonstrates preferential subcellular distribution to the oxidized environment of endoplasmic reticulum (ER).

Methodology/Principal Findings

Here we report that splicing of C-α1 sGC can be modulated by H2O2 treatment in BE2 neuroblastoma and MDA-MD-468 adenocarcinoma human cells. In addition, we show that the H2O2 treatment of MDA-MD-468 cells selectively …

Aspirin But Not Ibuprofen Use Is Associated With Reduced Risk Of Prostate Cancer: A Plco Study., F. M. Shebl, L. C. Sakoda, A. Black, J. Koshiol, G. L. Andriole, R. Grubb, T. R. Church, D. Chia, C. Zhou, L. W. Chu, W. Y. Huang, U. Peters, V. A. Kirsh, N. Chatterjee, M. F. Leitzmann, R. B. Hayes, A. W. Hsing

Biochemistry and Molecular Medicine Faculty Publications

Background:

Although most epidemiological studies suggest that non-steroidal anti-inflammatory drug use is inversely associated with prostate cancer risk, the magnitude and specificity of this association remain unclear.

Methods:

We examined self-reported aspirin and ibuprofen use in relation to prostate cancer risk among 29 450 men ages 55–74 who were initially screened for prostate cancer from 1993 to 2001 in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Men were followed from their first screening exam until 31 December 2009, during which 3575 cases of prostate cancer were identified.

Results:

After adjusting for potential confounders, the hazard ratios (HRs) of …

Proteome-Wide Analysis Of Single-Nucleotide Variations In The N-Glycosylation Sequon Of Human Genes, Raja Mazumder, Krishna Sudeep Morampudi, Mona Motwani, Sona Vasudevan, Radoslav Goldman

Biochemistry and Molecular Medicine Faculty Publications

N-linked glycosylation is one of the most frequent post-translational modifications of proteins with a profound impact on their biological function. Besides other functions, N-linked glycosylation assists in protein folding, determines protein orientation at the cell surface, or protects proteins from proteases. The N-linked glycans attach to asparagines in the sequence context Asn-X-Ser/Thr, where X is any amino acid except proline. Any variation (e.g. non-synonymous single nucleotide polymorphism or mutation) that abolishes the N-glycosylation sequence motif will lead to the loss of a glycosylation site. On the other hand, variations causing a substitution that creates a new N-glycosylation sequence motif can …

Development Stage-Specific Proteomic Profiling Uncovers Small, Lineage Specific Proteins Most Abundant In The Aspergillus Fumigatus Conidial Proteome, Moo-Jin Suh, Natalie D. Fedorova, Steven E. Cagas, Susan Hastings, Robert D. Fleischmann, Scott N. Peterson, David S. Perlin, William C. Nierman, Rembert Pieper, Michelle Momany

Biochemistry and Molecular Medicine Faculty Publications

Background

The pathogenic mold Aspergillus fumigatus is the most frequent infectious cause of death in severely immunocompromised individuals such as leukemia and bone marrow transplant patients. Germination of inhaled conidia (asexual spores) in the host is critical for the initiation of infection, but little is known about the underlying mechanisms of this process.

Results

To gain insights into early germination events and facilitate the identification of potential stage-specific biomarkers and vaccine candidates, we have used quantitative shotgun proteomics to elucidate patterns of protein abundance changes during early fungal development. Four different stages were examined: dormant conidia, isotropically expanding conidia, hyphae …

An Unexpected Function Of The Prader-Willi Syndrome Imprinting Center In Maternal Imprinting In Mice, Mei-Yi Wu, Ming Jiang, Xiaodong Zhang, Arthur L. Beaudet, Ray-Chang Wu

Biochemistry and Molecular Medicine Faculty Publications

Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11–q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted …

Histone Recognition And Large-Scale Structural Analysis Of The Human Bromodomain Family, Panagis Filippakopoulos, Sarah Picaud, Maria Mangos, Tracy Keates, Jean-Philippe Lambert, Dalia Barsyte-Lovejoy, Ildiko Felletar, Rudolf Volkmer, Susanne Muller, Tony Pawson, Anne-Claude Gingras, Cheryl H. Arrowsmith, Stefan Knapp

Biochemistry and Molecular Medicine Faculty Publications

Bromodomains (BRDs) are protein interaction modules that specifically recognize ε-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations …

Transcriptomic Landscape Of Breast Cancers Through Mrna Sequencing, Jeyanthy Eswaran, Dinesh Cyanam, Prakriti Mudvari, Sirigiri Divijendra Natha Reddy, Suresh Pakala, Sujit S. Nair, Liliana Florea, Suzanne A.W. Fuqua, Sucheta Godbole, Rakesh Kumar

Biochemistry and Molecular Medicine Faculty Publications

No abstract provided.

The Role Of Ezh2 In The Regulation Of The Activity Of Matrix Metalloproteinases In Prostate Cancer Cells., Yong Jae Shin, Jeong-Ho Kim

Biochemistry and Molecular Medicine Faculty Publications

Degradation of the extracellular matrix (ECM), a critical step in cancer metastasis, is determined by the balance between MMPs (matrix metalloproteinases) and their inhibitors TIMPs (tissue inhibitors of metalloproteinases). In cancer cells, this balance is shifted towards MMPs, promoting ECM degradation. Here, we show that EZH2 plays an active role in this process by repressing the expression of TIMP2 and TIMP3 in prostate cancer cells. The TIMPgenes are derepressed by knockdown of EZH2 expression in human prostate cancer cells but repressed by overexpression of EZH2 in benign human prostate epithelial cells. EZH2 catalyzes H3K27 trimethylation and subsequent DNA methylation …

The Role Of Ezh2 In The Regulation Of The Activity Of Matrix Metalloproteinases In Prostate Cancer Cells., Yong Jae Shin, Jeong-Ho Kim

Biochemistry and Molecular Medicine Faculty Publications

Degradation of the extracellular matrix (ECM), a critical step in cancer metastasis, is determined by the balance between MMPs (matrix metalloproteinases) and their inhibitors TIMPs (tissue inhibitors of metalloproteinases). In cancer cells, this balance is shifted towards MMPs, promoting ECM degradation. Here, we show that EZH2 plays an active role in this process by repressing the expression of TIMP2 and TIMP3 in prostate cancer cells. The TIMP genes are derepressed by knockdown of EZH2 expression in human prostate cancer cells but repressed by overexpression of EZH2 in benign human prostate epithelial cells. EZH2 catalyzes H3K27 trimethylation and subsequent DNA methylation …

Discovery Of Nitric Oxide And Cyclic Gmp In Cell Signaling And Their Role In Drug Development, Ferid Murad

Biochemistry and Molecular Medicine Faculty Publications

No abstract provided.

Recent Advances In Biocuration: Meeting Report From The Fifth International Biocuration Conference, Pascale Gaudet, Cecilia Arighi, Frederic Bastian, Alex Bateman, Judith A. Blake, Raja Mazumder, +17 Additional Authors

Biochemistry and Molecular Medicine Faculty Publications

The 5th International Biocuration Conference brought together over 300 scientists to exchange on their work, as well as discuss issues relevant to the International Society for Biocuration’s (ISB) mission. Recurring themes this year included the creation and promotion of gold standards, the need for more ontologies, and more formal interactions with journals. The conference is an essential part of the ISB's goal to support exchanges among members of the biocuration community. Next year's conference will be held in Cambridge, UK, from 7 to 10 April 2013. In the meanwhile, the ISB website provides information about the society's activities (http://biocurator.org …