Biochemistry, Biophysics, and Structural Biology Commons^™

Role Of Hepatitis C Virus Inducted Osteopontin In Epithelial To Mesenchymal Transition, Migration, And Invasion Of Hepatocytes, Jawed Iqbal, Steven Mcrae, Thi Mai, Krishna Banaudha, Mehuli Sarkar-Dutta, Gulam Waris

Biochemistry and Molecular Medicine Faculty Publications

Osteopontin (OPN) is a secreted phosphoprotein which has been linked to tumor progression and metastasis in a variety of cancers including hepatocellular carcinoma (HCC). Previous studies have shown that OPN is upregulated during liver injury and inflammation. However, the role of OPN in hepatitis C virus (HCV)-induced liver disease pathogenesis is not known. In this study, we determined the induction of OPN, and then investigated the effect of secreted forms of OPN in epithelial to mesenchymal transition (EMT), migration and invasion of hepatocytes. We show the induction of OPN mRNA and protein expression by HCV-infection. Our results also demonstrate the …

Non-Synonymous Variations In Cancer And Their Effects On The Human Proteome: Workflow For Ngs Data Biocuration And Proteome-Wide Analysis Of Tcga Data, Charles Cole, Konstantinos Krampis, Konstantinos Karagiannis, Jonas Almeida, William J. Faison, Mona Motwani, Quan Wan, Anton Golikov, Yang Pan, Vahan Simonyan, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

Background

Next-generation sequencing (NGS) technologies have resulted in petabytes of scattered data, decentralized in archives, databases and sometimes in isolated hard-disks which are inaccessible for browsing and analysis. It is expected that curated secondary databases will help organize some of this Big Data thereby allowing users better navigate, search and compute on it.

Results

To address the above challenge, we have implemented a NGS biocuration workflow and are analyzing short read sequences and associated metadata from cancer patients to better understand the human variome. Curation of variation and other related information from control (normal tissue) and case (tumor) samples will …

Understanding The Mechanism Of Glucose-Induced Relief Of Rgt1-Mediated Repression In Yeast, Adhiraj Roy, David Jouandot, Kyu Hong Cho, Jeong-Ho Kim

Biochemistry and Molecular Medicine Faculty Publications

The yeast Rgt1 repressor inhibits transcription of the glucose transporter (HXT) genes in the absence of glucose. It does so by recruiting the general corepressor complex Ssn6-Tup1 and the HXT corepressor Mth1. In the presence of glucose, Rgt1 is phosphorylated by the cAMP-activated protein kinase A (PKA) and dissociates from the HXT promoters, resulting in expression of HXT genes. In this study, using Rgt1 chimeras that bind DNA constitutively, we investigate how glucose regulates Rgt1 function. Our results show that the DNA-bound Rgt1 constructs repress expression of the HXT1 gene in conjunction with Ssn6-Tup1 and Mth1, and that …

A Framework For Organizing Cancer-Related Variations From Existing Databases, Publications And Ngs Data Using A High-Performance Integrated Virtual Environment (Hive), Tsung-Jung Wu, Amirhossein Shamsaddini, Yang Pan, Krista Smith, Daniel J. Chrichton, Vahan Simonyan, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

Years of sequence feature curation by UniProtKB/Swiss-Prot, PIR-PSD, NCBI-CDD, RefSeq and other database biocurators has led to a rich repository of information on functional sites of genes and proteins. This information along with variation-related annotation can be used to scan human short sequence reads from next-generation sequencing (NGS) pipelines for presence of non-synonymous single-nucleotide variations (nsSNVs) that affect functional sites. This and similar workflows are becoming more important because thousands of NGS data sets are being made available through projects such as The Cancer Genome Atlas (TCGA), and researchers want to evaluate their biomarkers in genomic data. BioMuta, an integrated …

High-Performance Integrated Virtual Environment (Hive) Tools And Applications For Big Data Analysis, Vahan Simonyan, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

The High-performance Integrated Virtual Environment (HIVE) is a high-throughput cloud-based infrastructure developed for the storage and analysis of genomic and associated biological data. HIVE consists of a web-accessible interface for authorized users to deposit, retrieve, share, annotate, compute and visualize Next-generation Sequencing (NGS) data in a scalable and highly efficient fashion. The platform contains a distributed storage library and a distributed computational powerhouse linked seamlessly. Resources available through the interface include algorithms, tools and applications developed exclusively for the HIVE platform, as well as commonly used external tools adapted to operate within the parallel architecture of the system. HIVE is …

Human Germline And Pan-Cancer Variomes And Their Distinct Functional Profiles, Yang Pan, Konstantinos Karagiannis, Haichen Zhang, Hayley Dingerdissen, Amirhossein Shamsaddini, Quan Wan, Vahan Simonyan, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

Identification of non-synonymous single nucleotide variations (nsSNVs) has exponentially increased due to advances in Next-Generation Sequencing technologies. The functional impacts of these variations have been difficult to ascertain because the corresponding knowledge about sequence functional sites is quite fragmented. It is clear that mapping of variations to sequence functional features can help us better understand the pathophysiological role of variations. In this study, we investigated the effect of nsSNVs on more than 17 common types of post-translational modification (PTM) sites, active sites and binding sites. Out of 1 705 285 distinct nsSNVs on 259 216 functional sites we identified 38 …

Alpha-Asarone Protects Endothelial Cells From Injury By Angiotensin Ii, Ha-Xia Shi, Jiajun Yang, Tao Yang, Yong-Liang Xue, Jun Liu, Ya-Juan Li, Dan-Dan Zhang, Ji-Wen Zhu, Ka Bian

Biochemistry and Molecular Medicine Faculty Publications

α-Asarone is the major therapeutical constituent of Acorus tatarinowii Schott. In this study, the potential protective effects of α-asarone against endothelial cell injury induced by angiotensin II were investigated in vitro. The EA.hy926 cell line derived from human umbilical vein endothelial cells was pretreated with α-asarone (10, 50, 100 µmol/L) for 1 h, followed by coincubation with Ang II (0.1 µmol/L) for 24 h. Intracellular nitric oxide (NO) and reactive oxygen species (ROS) were detected by fluorescent dyes, and phosphorylation of endothelial nitric oxide synthase (eNOS) at was determined by Western blotting. α-Asarone dose-dependently mitigated the Ang II-induced intracellular NO …

Census-Based Rapid And Accurate Metagenome Taxonomic Profiling, Amirhossein Shamsaddini, Yang Pan, W. Evan Johnson, Konstantinos Krampis, Mariya Shcheglovitova, Vahan Simonyan, Amy Zanne, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

Background

Understanding the taxonomic composition of a sample, whether from patient, food or environment, is important to several types of studies including pathogen diagnostics, epidemiological studies, biodiversity analysis and food quality regulation. With the decreasing costs of sequencing, metagenomic data is quickly becoming the preferred typed of data for such analysis.

Results

Rapidly defining the taxonomic composition (both taxonomic profile and relative frequency) in a metagenomic sequence dataset is challenging because the task of mapping millions of sequence reads from a metagenomic study to a non-redundant nucleotide database such as the NCBI non-redundant nucleotide database (nt) is a computationally intensive …

Single-Nucleotide Variations In Cardiac Arrhythmias: Prospects For Genomics And Proteomics Based Biomarker Discovery And Diagnostics, Ayman Abunimer, Krista Smith, Tsung-Jung Wu, Phuc Lam, Vahan Simonyan, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

Cardiovascular diseases are a large contributor to causes of early death in developed countries. Some of these conditions, such as sudden cardiac death and atrial fibrillation, stem from arrhythmias—a spectrum of conditions with abnormal electrical activity in the heart. Genome-wide association studies can identify single nucleotide variations (SNVs) that may predispose individuals to developing acquired forms of arrhythmias. Through manual curation of published genome-wide association studies, we have collected a comprehensive list of 75 SNVs associated with cardiac arrhythmias. Ten of the SNVs result in amino acid changes and can be used in proteomic-based detection methods. In an effort to …

Comparative Lipid Profiles Of Milk Bank Breast Milk And Infant Formulas, Anya Oleynik, Tatiana Eliseeva, Jack Y. Vanderhoek

Biochemistry and Molecular Medicine Faculty Publications

Lipid profiles of seven human breast milk samples obtained from milk banks and four infant formulas were compared in view of the potential food hypersensitivities of certain infants to human milk.The cholesterol (0.15-0.26 mM) content of the human samples was about 50% lower than that found in the infant formulas whereas the triglyceride (TG, 173-386 mM) contents of these products were found to be comparable.The major saturated fatty acid (SFA) and mono-unsaturated fatty acid (MUFA) were 16:0 and 18:1 respectively. The major poly-unsaturated fatty acid (PUFA) was 18:2 with otherPUFA members of the C18, C20 and C22 families identified and …

Draft Genome Sequences Of Burkholderia Cenocepacia Et12 Lineage Strains K56-2 And Bc7, John J. Varga, Liliana Losada, Adrian M. Zelazny, Maria Kim, Jamison Mccorrison, Lauren Brinkac, Elizabeth P. Sampaio, David E. Greenberg, Indresh Singh, Cheryl Heiner, Meredith Ashby, William C. Nierman, Steven M. Holland, Joanna B. Goldberg

Biochemistry and Molecular Medicine Faculty Publications

The Burkholderia cepacia complex (BCC) is a group of closely related bacteria that are responsible for respiratory infections in immunocompromised humans, most notably those with cystic fibrosis (CF). We report the genome sequences forBurkholderia cenocepacia ET12 lineage CF isolates K56-2 and BC7.

Differential Recruitment Of Coregulators To The Rora Promoter Adds Another Layer Of Complexity To Gene (Dys)Regulation By Sex Hormones In Autism, Tewarit Sarachana, Valerie Wailin Hu

Biochemistry and Molecular Medicine Faculty Publications

Background

Our independent cohort studies have consistently shown the reduction of the nuclear receptor RORA (retinoic acid-related orphan receptor-alpha) in lymphoblasts as well as in brain tissues from individuals with autism spectrum disorder (ASD). Moreover, we have found that RORA regulates the gene for aromatase, which converts androgen to estrogen, and that male and female hormones regulate RORA in opposite directions, with androgen suppressing RORA, suggesting that the sexually dimorphic regulation of RORA may contribute to the male bias in ASD. However, the molecular mechanisms through which androgen and estrogen differentially regulate RORA are still unknown.

Methods

Here we use …

Identification Of Novel Gene Targets And Functions Of P21-Activated Kinase 1 During Dna Damage By Gene Expression Profiling, Mona Motwani, Da-Qiang Li, Anelia Horvath, Rakesh Kumar

Biochemistry and Molecular Medicine Faculty Publications

P21-activated kinase 1 (PAK1), a serine/threonine protein kinase, modulates many cellular processes by phosphorylating its downstream substrates. In addition to its role in the cytoplasm, PAK1 also affects gene transcription due to its nuclear localization and association with chromatin. It is now recognized that PAK1 kinase activity and its nuclear translocation are rapidly stimulated by ionizing radiation (IR), and that PAK1 activation is a component of the DNA damage response. Owing to the role of PAK1 in the cell survival, its association with the chromatin, and now, stimulation by ionizing radiation, we hypothesize that PAK1 may be contributing to modulation …

Evidence For A Novel Mechanism Of The Pak1 Interaction With The Rho-Gtpases Cdc42 And Rac, Yong Jae Shin, Eun Hye Kim, Adhiraj Roy, Jeong-Ho Kim

Biochemistry and Molecular Medicine Faculty Publications

P21-activated kinase 1 (PAK1) is activated by binding to GTP-bound Rho GTPases Cdc42 and Rac via its CRIB domain. Here, we provide evidence that S79 in the CRIB domain of PAK1 is not directly involved in this binding but is crucial for PAK1 activation. S79A mutation reduces the binding affinity of PAK1 for the GTPases and inhibits autophosphorylation and kinase activity of PAK1. Thus, this mutation abrogates the ability of PAK1 to induce changes in cell morphology and motility and to promote malignant transformation of prostate epithelial cells. We also show that growth of the prostate cancer cell line PC3 …

Dna Homologous Recombination Factor Sfr1 Physically And Functionally Interacts With Estrogen Receptor Alpha, Yuxin Feng, David Singleton, Chun Guo, Amanda Gardner, Suresh Pakala, Rakesh Kumar, Elwood Jensen, Jinsong Zhang, Sohaib Khan

Biochemistry and Molecular Medicine Faculty Publications

Estrogen receptor alpha (ERα), a ligand-dependent transcription factor, mediates the expression of its target genes by interacting with corepressors and coactivators. Since the first cloning of SRC1, more than 280 nuclear receptor cofactors have been identified, which orchestrate target gene transcription. Aberrant activity of ER or its accessory proteins results in a number of diseases including breast cancer. Here we identified SFR1, a protein involved in DNA homologous recombination, as a novel binding partner of ERα. Initially isolated in a yeast two-hybrid screen, the interaction of SFR1 and ERα was confirmed in vivo by immunoprecipitation and mammalian one-hybrid assays. SFR1 …

A Novel Stratification Method In Linkage Studies To Address Inter- And Intra-Family Heterogeneity In Autism, Zohreh Talebizadeh, Dan E. Arking, Valerie Wailin Hu

Biochemistry and Molecular Medicine Faculty Publications

Most genome linkage scans for autism spectrum disorders (ASDs) have failed to be replicated. Recently, a new ASD phenotypic sub-classification method was developed which employed cluster analyses of severity scores from the Autism Diagnostic Interview-Revised (ADI-R). Here, we performed linkage analysis for each of the four identified ADI-R stratified subgroups. Additional stratification was also applied to reduce intra-family heterogeneity and to investigate the impact of gender. For the purpose of replication, two independent sets of single nucleotide polymorphism markers for 392 families were used in our study. This deep subject stratification protocol resulted in 16 distinct group-specific datasets for linkage …

Novel Regulatory Small Rnas In Streptococcus Pyogenes, Rafael A. Tesorero, Ning Yu, Jordan O. Wright, Juan P. Svencionis, Qiang Cheng, Jeong-Ho Kim, Kyu Hong Cho

Biochemistry and Molecular Medicine Faculty Publications

Streptococcus pyogenes (Group A Streptococcus or GAS) is a Gram-positive bacterial pathogen that has shown complex modes of regulation of its virulence factors to cause diverse diseases. Bacterial small RNAs are regarded as novel widespread regulators of gene expression in response to environmental signals. Recent studies have revealed that several small RNAs (sRNAs) have an important role in S. pyogenes physiology and pathogenesis by regulating gene expression at the translational level. To search for new sRNAs in S. pyogenes, we performed a genomewide analysis through computational prediction followed by experimental verification. To overcome the limitation of low accuracy in …

Clinical And Technical Factors Associated With Skin Intrinsic Fluorescence In Subjects With Type 1 Diabetes From The Diabetes Control And Complications Trial/Epidemiology Of Diabetes Interventions And Complications Study, Patricia A. Cleary, Barbara H. Braffett, Trevor J. Orchard, Timothy J. Lyons, John D. Maynard, Catherine C. Cowie, Rose A. Gubitosi-Klug, Jeff F. Way, Karen L. Anderson, Annette Barnie, Stephan Villavicencio

Biochemistry and Molecular Medicine Faculty Publications

Background: The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) studies have established multiyear mean hemoglobin A1c (HbA1c) as predictive of microvascular complications in persons with type 1 diabetes. However, multiyear mean HbA1c is not always available in the clinical setting. Skin advanced glycation end products (AGEs) are thought to partially reflect effects of hyperglycemia over time, and measurement of skin AGEs might be a surrogate for multiyear mean HbA1c. As certain AGEs fluoresce and skin fluorescence has been demonstrated to correlate with the concentration of skin AGEs, noninvasive measurement by skin intrinsic fluorescence (SIF) facilitates …

Ckap2 Ensures Chromosomal Stability By Maintaining The Integrity Of Microtubule Nucleation Sites, Chanelle M. Case, Dan L. Sackett, Danny Wangsa, Tatiana S. Karpova, James G. Mcnally, Thomas Ried, Jordi Camps

Biochemistry and Molecular Medicine Faculty Publications

Integrity of the microtubule spindle apparatus and intact cell division checkpoints are essential to ensure the fidelity of distributing chromosomes into daughter cells. Cytoskeleton-associated protein 2, CKAP2, is a microtubule-associated protein that localizes to spindle poles and aids in microtubule stabilization, but the exact function and mechanism of action are poorly understood. In the present study, we utilized RNA interference to determine the extent to which the expression of CKAP2 plays a role in chromosome segregation. CKAP2-depleted cells showed a significant increase of multipolar mitoses and other spindle pole defects. Notably, when interrogated for microtubule nucleation capacity, CKAP2-depleted cells showed …

Genome-Wide Identification Of Transcriptional Targets Of Rora Reveals Direct Regulation Of Multiple Genes Associated With Autism Spectrum Disorder, Tewarit Sarachana, Valerie Wailin Hu

Biochemistry and Molecular Medicine Faculty Publications

No abstract provided.

Mth1 Regulates The Interaction Between The Rgt1 Repressor And The Ssn6-Tup1 Corepressor Complex By Modulating Pka-Dependent Phosphorylation Of Rgt1, Adhiraj Roy, Yong Jae Shin, Kyu Hong Cho, Jeong-Ho Kim

Biochemistry and Molecular Medicine Faculty Publications

Glucose uptake, the first, rate-limiting step of its utilization, is facilitated by glucose transporters. Expression of several glucose transporter (HXT) genes in yeast is repressed by the Rgt1 repressor, which recruits the glucose-responsive transcription factor Mth1 and the general corepressor complex Ssn6-Tup1 in the absence of glucose; however, it is derepressed when Mth1 is inactivated by glucose. Here we show that Ssn6-Tup1 interferes with the DNA-binding ability of Rgt1 in the absence of Mth1 and that the Rgt1 function abrogated by Ssn6 overexpression is restored by co-overexpression of Mth1. Thus Mth1 likely regulates Rgt1 function not by modulating …

Rna Sequencing Of Cancer Reveals Novel Splicing Alterations, Jeyanthy Eswaran, Anelia Horvath, Sucheta Godbole, Sirigiri Divijendra Natha Reddy, Prakriti Mudvari, Kazufumi Ohshiro, Dinesh Cyanam, Sujit S. Nair, Suzanne A.W. Fuqua, Kornelia Polyak, Liliana D. Florea, Rakesh Kumar

Biochemistry and Molecular Medicine Faculty Publications

Breast cancer transcriptome acquires a myriad of regulation changes, and splicing is critical for the cell to “tailor-make” specific functional transcripts. We systematically revealed splicing signatures of the three most common types of breast tumors using RNA sequencing: TNBC, non-TNBC and HER2-positive breast cancer. We discovered subtype specific differentially spliced genes and splice isoforms not previously recognized in human transcriptome. Further, we showed that exon skip and intron retention are predominant splice events in breast cancer. In addition, we found that differential expression of primary transcripts and promoter switching are significantly deregulated in breast cancer compared to normal breast. We …

A Positive Feedback Loop Regulates The Expression Of Polycomb Group Protein Bmi1 Via Wnt Signaling Pathway, Joon-Ho Cho, Manjari Dimri, Goberdhan P. Dimri

Biochemistry and Molecular Medicine Faculty Publications

Polycomb group protein BMI1 plays an important role in cellular homeostasis by maintaining a balance between proliferation and senescence. It is often overexpressed in cancer cells and is required for self-renewal of stem cells. At present, very little is known about the signaling pathways that regulate the expression of BMI1. Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter. We show that BMI1 acts as an activator of the WNT pathway by repressing Dickkopf (DKK) family of WNT inhibitors. BMI1 mediated repression of DKK proteins; in particular, DKK1 led to up-regulation of WNT …

Acidic Nucleoplasmic Dna-Binding Protein (And-1) Controls Chromosome Congression By Regulating The Assembly Of Centromere Protein A (Cenp-A) At Centromeres, Aimee Jaramillo-Lambert, Jing Hao, Haijie Xiao, Yongming Li, Zhiyong Han, Wenge Zhu

Biochemistry and Molecular Medicine Faculty Publications

Background: The incorporation of CENP-A at centromeres is important for chromosome segregation during mitosis.

Results: And-1 together with HJURP regulates the assembly of new CENP-A onto centromeres.

Conclusion: And-1 facilitates the recruitment of CENP-A to centromeres.

Significance: These studies reveal a novel role of And-1 in the regulation of chromosome congression during mitosis.

A Comprehensive, Multi-Scale Dynamical Model Of Erbb Receptor Signal Transduction In Human Mammary Epithelial Cells, Tomas Helikar, Naomi Kochi, Bryan Kowal, Manjari Dimri, Mayumy Naramura, Srikumar M. Raja, Vimla Band, Hamid Band, Jim A. Rogers

Biochemistry and Molecular Medicine Faculty Publications

The non-receptor tyrosine kinase Src and receptor tyrosine kinase epidermal growth factor receptor (EGFR/ErbB1) have been established as collaborators in cellular signaling and their combined dysregulation plays key roles in human cancers, including breast cancer. In part due to the complexity of the biochemical network associated with the regulation of these proteins as well as their cellular functions, the role of Src in EGFR regulation remains unclear. Herein we present a new comprehensive, multi-scale dynamical model of ErbB receptor signal transduction in human mammary epithelial cells. This model, constructed manually from published biochemical literature, consists of 245 nodes representing proteins …

Novel Insights Into Breast Cancer Genetic Variance Through Rna Sequencing, Anelia Horvath, Suresh B. Pakala, Prakriti Mudvari, Sirigiri Divijendra Natha Reddy, Kazufumi Ohshiro, Sandra Casimiro, Ricardo Pires, Suzanne A.W. Fuqua, Masakazu Toi, Luis Costa, Sujit S. Nair, Saraswati Sukumar, Rakesh Kumar

Biochemistry and Molecular Medicine Faculty Publications

Using RNA sequencing of triple-negative breast cancer (TNBC), non-TBNC and HER2-positive breast cancer sub-types, here we report novel expressed variants, allelic prevalence and abundance, and coexpression with other variation, and splicing signatures. To reveal the most prevalent variant alleles, we overlaid our findings with cancer- and population-based datasets and validated a subset of novel variants of cancer-related genes: ESRP2, GBP1, TPP1, MAD2L1BP, GLUD2 and SLC30A8. As a proof-of-principle, we demonstrated that a rare substitution in the splicing coordinator ESRP2(R353Q) impairs its ability to bind to its substrate FGFR2 pre-mRNA. In addition, we describe novel SNPs and INDELs in …

Community Annotation And The Evolution Of Cooperation: How Patience Matters, Atin Basuchoudhary, Vahan Simoyan, Raja Mazumder

Biochemistry and Molecular Medicine Faculty Publications

We investigate why biologists fail to contribute to biological databases although almost all of them use these databases for research. We find, using evolutionary game theory and computer simulations, that (a) the initial distribution of contributors who are patient determines whether a culture of contribution will prevail or not (b) institutions (where institution means “a significant practice, relationship, or organization in a society or culture”) that incentivize patience and therefore limit free riding make contribution more likely and, (c) a stable institution, whether it incentivizes patience or not, will increase contribution. As a result we suggest there is a trade-off …

Extraction Of Molecular Features Through Exome To Transcriptome Alignment, Prakriti Mudvari, Kamran Kowsari, Charles Cole, Raja Mazumder, Anelia Horvath

Biochemistry and Molecular Medicine Faculty Publications

Integrative Next Generation Sequencing (NGS) DNA and RNA analyses have very recently become feasible, and the published to date studies have discovered critical disease implicated pathways, and diagnostic and therapeutic targets. A growing number of exomes, genomes and transcriptomes from the same individual are quickly accumulating, providing unique venues for mechanistic and regulatory features analysis, and, at the same time, requiring new exploration strategies. In this study, we have integrated variation and expression information of four NGS datasets from the same individual: normal and tumor breast exomes and transcriptomes. Focusing on SNP-centered variant allelic prevalence, we illustrate analytical algorithms that …

Morc2 Signaling Integrates Phosphorylation-Dependent, Atpase-Coupled Chromatin Remodeling During The Dna Damage Response, Da-Qiang Li, Sujit S. Nair, Kazufumi Ohshiro, Anupam Kumar, Vasudha S. Nair, Suresh B. Pakala, Sirigiri Divijendra Natha Reddy, Rajendra P. Gajula, Jeyanthy Eswaran, L. Aravind, Rakesh Kumar

Biochemistry and Molecular Medicine Faculty Publications

Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1-dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. …

P21-Activated Kinase-1 Signaling Regulates Transcription Of Tissue Factor And Tissue Factor Pathway Inhibitor., Beatriz Sanchez-Solana, Mona Motwani, Da-Qiang Li, Jeyanthy Eswaran, Rakesh Kumar

Biochemistry and Molecular Medicine Faculty Publications

Tissue factor (TF) is a cell-surface glycoprotein responsible for initiating the coagulation cascade. Besides its role in homeostasis, studies have shown the implication of TF in embryonic development, cancer related events, and inflammation via coagulation-dependent and -independent (signaling) mechanisms. Tissue factor pathway inhibitor (TFPI) plays an important role in regulating TF-initiated blood coagulation. Therefore, transcriptional regulation of TF expression and its physiologic inhibitor TFPI, would allow us to understand the critical step that control many different processes. From a gene profiling study aimed to identify differentially regulated genes between wild type (WT) and p21-activated kinase 1-null (PAK1-KO) mouse embryonic fibroblasts …