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Nupam P Mahajan, Domenico Coppola, Jongphil Kim, Harshani R Lawrence, Nicholas J Lawrence, Kiran Mahajan
Prostate cancer stem-like cells (PCSCs) are not only enriched in the CD44+ PSA-/lo subpopulation but also employ androgen-independent signaling mechanisms for survival. CD44+ PCSCs defy androgen deprivation, resist chemo- and radiotherapy and are highly tumorigenic. Human prostate tissue microarray (TMA) staining revealed an increased membranous staining of CD44 in the luminal compartment in higher grade G7-G9 tumors versus staining of the basal layer in benign hyperplasia. To uncover tyrosine kinase/s critical for the survival of the CD44+ PSA-/lo subpopulation, we performed an unbiased screen targeting 87 tyrosine kinases with gene specific siRNAs...
January 31, 2018: Scientific Reports
Hongbing Jiang, Kevin Chen, Luis E Sandoval, Christian Leung, David Wang
Many fundamental biological discoveries have been made in Caenorhabditis elegans The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP) reporter. Following chemical mutagenesis, two Viro (virus induced reporter off) mutants that failed to express GFP were mapped to sid-3, a nonreceptor tyrosine kinase, and B0280...
September 5, 2017: MBio
Michał Korostyński, Natalia Małek, Marcin Piechota, Katarzyna Starowicz
Biomarkers of osteoarthritis (OA) that can accurately diagnose the disease at the earliest stage would significantly support efforts to develop treatments for prevention and early intervention. We have sought to determine the time course of alterations in peripheral blood gene expression profile associated with the development of OA. Blood samples were collected from a tail vein of individual rats with monosodium iodoacetate- (MIA-) induced OA (2, 14, 21, and 28 days after the treatment). We used whole-genome microarrays to reveal OA-related transcriptional alterations of 72 transcripts...
2017: International Journal of Genomics
Nisintha Mahendrarajah, Marina E Borisova, Sigrid Reichardt, Maren Godmann, Andreas Sellmer, Siavosh Mahboobi, Andrea Haitel, Katharina Schmid, Lukas Kenner, Thorsten Heinzel, Petra Beli, Oliver H Krämer
Signal transducers and activators of transcription (STATs) are latent, cytoplasmic transcription factors. Janus kinases (JAKs) and activated CDC42-associated kinase-1 (ACK1/TNK2) catalyse the phosphorylation of STAT1 and the expression of its target genes. Here we demonstrate that catalytically active ACK1 promotes the phosphorylation and nuclear accumulation of STAT1 in transformed kidney cells. These processes are associated with STAT1-dependent gene expression and an interaction between endogenous STAT1 and ACK1...
November 2017: Cellular Signalling
Kiran Mahajan, Pavani Malla, Harshani R Lawrence, Zhihua Chen, Chandan Kumar-Sinha, Rohit Malik, Sudhanshu Shukla, Jongphil Kim, Domenico Coppola, Nicholas J Lawrence, Nupam P Mahajan
The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription...
June 12, 2017: Cancer Cell
Emeline Gauthiez, Ines Habfast-Robertson, Sina Rüeger, Zoltan Kutalik, Vincent Aubert, Thomas Berg, Andreas Cerny, Meri Gorgievski, Jacob George, Markus H Heim, Raffaele Malinverni, Darius Moradpour, Beat Müllhaupt, Francesco Negro, David Semela, Nasser Semmo, Jean Villard, Stéphanie Bibert, Pierre-Yves Bochud
While hepatitis C exemplifies the role of host genetics in infectious diseases outcomes, there is no comprehensive overview of polymorphisms influencing spontaneous and/or treatment-induced hepatitis C virus clearance. We performed a systematic review and meta-analysis of host polymorphisms associated with these phenotypes. Literature search was conducted using combinations of keywords in three databases. Studies were reviewed and relevant data systematically extracted for subsequent meta-analyses. Polymorphisms from candidate gene studies were tested in two cohorts of HCV-infected patients with available genomic data...
October 2017: Liver International: Official Journal of the International Association for the Study of the Liver
Youg R Thaker, Asha Recino, Monika Raab, Asma Jabeen, Maja Wallberg, Nelson Fernandez, Christopher E Rudd
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, "3Y") as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76...
April 14, 2017: Journal of Biological Chemistry
Xinyan Wu, Muhammad Saddiq Zahari, Santosh Renuse, Dhanashree S Kelkar, Mustafa A Barbhuiya, Pamela L Rojas, Vered Stearns, Edward Gabrielson, Pavani Malla, Saraswati Sukumar, Nupam P Mahajan, Akhilesh Pandey
Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines...
January 10, 2017: Oncotarget
Nisintha Mahendrarajah, Ramin Paulus, Oliver H Krämer
PURPOSE: Activated CDC42-associated kinase-1 (ACK1/TNK2) and epigenetic regulators of the histone deacetylase (HDAC) family regulate the proliferation and survival of leukemic cells. 18 HDACs fall into four classes (I-IV). We tested the impact of clinically relevant histone deacetylase inhibitors (HDACi) on ACK1 and if such drugs combine favorably with the therapeutically used ACK1 inhibitor Dasatinib. METHODS: We applied the broad-range HDACi Panobinostat/LBH589 and the class I HDAC-specific inhibitor Entinostat/MS-275 to various acute and chronic myeloid leukemia cells (AML/CML)...
November 2016: Journal of Cancer Research and Clinical Oncology
Gajanan Sathe, Sneha M Pinto, Nazia Syed, Vishalakshi Nanjappa, Hitendra S Solanki, Santosh Renuse, Sandip Chavan, Aafaque Ahmad Khan, Arun H Patil, Raja Sekhar Nirujogi, Bipin Nair, Premendu Prakash Mathur, T S Keshava Prasad, Harsha Gowda, Aditi Chatterjee
BACKGROUND: Curcumin, derived from the rhizome Curcuma longa, is a natural anti-cancer agent and has been shown to inhibit proliferation and survival of tumor cells. Although the anti-cancer effects of curcumin are well established, detailed understanding of the signaling pathways altered by curcumin is still lacking. In this study, we carried out SILAC-based quantitative proteomic analysis of a HNSCC cell line (CAL 27) to investigate tyrosine signaling in response to curcumin. RESULTS: Using high resolution Orbitrap Fusion Tribrid Fourier transform mass spectrometer, we identified 627 phosphotyrosine sites mapping to 359 proteins...
2016: Clinical Proteomics
Julia E Maxson, Melissa L Abel, Jinhua Wang, Xianming Deng, Sina Reckel, Samuel B Luty, Huahang Sun, Julie Gorenstein, Seamus B Hughes, Daniel Bottomly, Beth Wilmot, Shannon K McWeeney, Jerald Radich, Oliver Hantschel, Richard E Middleton, Nathanael S Gray, Brian J Druker, Jeffrey W Tyner
The amount of genomic information about leukemia cells currently far exceeds our overall understanding of the precise genetic events that ultimately drive disease development and progression. Effective implementation of personalized medicine will require tools to distinguish actionable genetic alterations within the complex genetic landscape of leukemia. In this study, we performed kinase inhibitor screens to predict functional gene targets in primary specimens from patients with acute myeloid leukemia and chronic myelomonocytic leukemia...
January 1, 2016: Cancer Research
Janice L Farlow, Laurie A Robak, Kurt Hetrick, Kevin Bowling, Eric Boerwinkle, Zeynep H Coban-Akdemir, Tomasz Gambin, Richard A Gibbs, Shen Gu, Preti Jain, Joseph Jankovic, Shalini Jhangiani, Kaveeta Kaw, Dongbing Lai, Hai Lin, Hua Ling, Yunlong Liu, James R Lupski, Donna Muzny, Paula Porter, Elizabeth Pugh, Janson White, Kimberly Doheny, Richard M Myers, Joshua M Shulman, Tatiana Foroud
IMPORTANCE: Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors. OBJECTIVE: To identify genetic variants contributing to disease risk in familial PD. DESIGN, SETTING, AND PARTICIPANTS: A 2-stage study design that included a discovery cohort of families with PD and a replication cohort of familial probands was used. In the discovery cohort, rare exonic variants that segregated in multiple affected individuals in a family and were predicted to be conserved or damaging were retained...
January 2016: JAMA Neurology
Patrick Coit, Paul Renauer, Matlock A Jeffries, Joan T Merrill, W Joseph McCune, Kathleen Maksimowicz-McKinnon, Amr H Sawalha
Systemic lupus erythematosus is a multi-system disease characterized by wide-spread DNA methylation changes. To identify epigenetic susceptibility loci for lupus nephritis, genome-wide DNA methylation changes in naïve CD4+ T cells were compared between two sets of lupus patients with and without a history of renal involvement. A total of 56 lupus patients (28 with renal involvement and 28 without renal involvement), and 56 age-, sex-, and ethnicity-matched healthy controls were included in our study. We identified 191 CG sites and 121 genes that were only differentially methylated in lupus patients with but not without a history of renal involvement...
July 2015: Journal of Autoimmunity
Harshani R Lawrence, Kiran Mahajan, Yunting Luo, Daniel Zhang, Nathan Tindall, Miles Huseyin, Harsukh Gevariya, Sakib Kazi, Sevil Ozcan, Nupam P Mahajan, Nicholas J Lawrence
The tyrosine kinase ACK1, a critical signal transducer regulating survival of hormone-refractory cancers, is an important therapeutic target, for which there are no selective inhibitors in clinical trials to date. This work reports the discovery of novel and potent inhibitors for ACK1 tyrosine kinase (also known as TNK2) using an innovative fragment-based approach. Focused libraries were designed and synthesized by selecting fragments from reported ACK inhibitors to create hybrid structures in a mix and match process...
March 26, 2015: Journal of Medicinal Chemistry
Altangerel Otgonbat, Mingfeng Zhao
OBJECTIVE: To review the implications for diagnosis, pathogenesis and potential for new therapeutic option for chronic neutrophilic leukemia (CNL). DATA SOURCES: Data cited in this review were obtained mainly from PubMed and Medline from 1993 to 2013 and highly regarded older publications were also included. The terms "chronic neutrophilic leukemia" and "diagnosis" were used for the literature search. STUDY SELECTION: We identified, retrieved and reviewed the information on the clinical and laboratory features, the new genetic findings, prognosis and disease evolution and management of CNL...
2014: Chinese Medical Journal
Meghan L Rudd, Hassan Mohamed, Jessica C Price, Andrea J O'Hara, Matthieu Le Gallo, Mary Ellen Urick, Pedro Cruz, Suiyuan Zhang, Nancy F Hansen, Andrew K Godwin, Dennis C Sgroi, Tyra G Wolfsberg, James C Mullikin, Maria J Merino, Daphne W Bell
BACKGROUND: Endometrial cancer (EC) is the 8th leading cause of cancer death amongst American women. Most ECs are endometrioid, serous, or clear cell carcinomas, or an admixture of histologies. Serous and clear ECs are clinically aggressive tumors for which alternative therapeutic approaches are needed. The purpose of this study was to search for somatic mutations in the tyrosine kinome of serous and clear cell ECs, because mutated kinases can point to potential therapeutic targets. METHODS: In a mutation discovery screen, we PCR amplified and Sanger sequenced the exons encoding the catalytic domains of 86 tyrosine kinases from 24 serous, 11 clear cell, and 5 mixed histology ECs...
November 26, 2014: BMC Cancer
K Mahajan, N P Mahajan
Deregulated tyrosine kinase signaling alters cellular homeostasis to drive cancer progression. The emergence of a non-receptor tyrosine kinase (non-RTK), ACK1 (also known as activated Cdc42-associated kinase 1 or TNK2) as an oncogenic kinase, has uncovered novel mechanisms by which tyrosine kinase signaling promotes cancer progression. Although early studies focused on ACK1 as a cytosolic effector of activated transmembrane RTKs, wherein it shuttles between the cytosol and the nucleus to rapidly transduce extracellular signals from the RTKs to the intracellular effectors, recent data unfold a new aspect of its functionality as an epigenetic regulator...
August 6, 2015: Oncogene
Jiannan Zhang, Tao Chen, Qin Mao, Jinbo Lin, Jun Jia, Shanquan Li, Wenhao Xiong, Yingying Lin, Zhiqiang Liu, Xiaoyu Liu, Hailiang Zhao, Guisong Wang, Duo Zheng, Shuqi Qiu, Jianwei Ge
Aberrant PDGF-PDGFR signaling and its effects on downstream effectors have been implicated in glioma development. A crucial AKT regulator, ACK1 (TNK2) has been shown to be a downstream mediator of PDGF signaling; however, the exact underlying mechanisms in gliomas remain elusive. Here, we report that in glioma cells, PDGFR-β activation enhanced the interaction between ACK1 and AKT, resulting in AKT activation. PDGF treatment consistently promoted the formation of complexes containing PDGFR-β and ACK1. Mutational analysis suggested that Y635 of ACK1 is a PDGFR-β phosphorylation site and that the ACK1 Y635F mutant abrogated the sequential activation of AKT...
April 15, 2015: International Journal of Cancer. Journal International du Cancer
Kiran Mahajan, Harshani R Lawrence, Nicholas J Lawrence, Nupam P Mahajan
Hormone therapy with the selective estrogen-receptor modulator tamoxifen provides a temporary relief for patients with estrogen receptor α (ER)-positive breast cancers. However, a subset of patients exhibiting overexpression of the HER2 receptor tyrosine kinase displays intrinsic resistance to tamoxifen therapy. Therefore, elucidating the mechanisms promoting the estrogen (E2)-independent ER-regulated gene transcription in tamoxifen-resistant breast tumors is essential to identify new therapeutic avenues to overcome drug resistance and ameliorate poor prognosis...
October 10, 2014: Journal of Biological Chemistry
Khairun I Abdul-Jalil, Katherine M Sheehan, Sinead Toomey, Jasmin Schmid, Jochen Prehn, Anthony O'Grady, Robert Cummins, Brian O'Neill, Deborah A McNamara, Joseph Deasy, Oscar Breathnach, Liam Grogan, Ailin Rogers, Glen Doherty, Des Winter, John Ryan, Sherif El-Masry, David Gibbons, Kieran Sheahan, Peter Gillen, Elaine W Kay, Bryan T Hennessy
BACKGROUND: Locally advanced rectal cancer (LARC: T3/4 and/or node-positive) is treated with preoperative/neoadjuvant chemoradiotherapy (CRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP kinase (MAPK), and related pathways are implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic mutations in these pathways and LARC clinical outcomes. METHODS: We genotyped 234 potentially clinically relevant nonsynonymous mutations in 33 PI3K and MAPK pathway-related genes, including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET, and NRAS, using the Sequenom platform...
August 2014: Annals of Surgical Oncology
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