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Lili Zhang, Marianne Gallup, Lorna Zlock, Yu Ting Feeling Chen, Walter E Finkbeiner, Nancy A McNamara
Lung cancer is the leading cause of cancer-related death, and 87% of these deaths are directly attributable to smoking. Using three-dimensional cultures of primary human bronchial epithelial cells, we demonstrated that loss of adherens junction protein, epithelial cadherin, and the aberrant interaction of its adherens junction binding partner, p120-catenin (p120ctn), with the cytoplasmic tail of apical mucin-1 (MUC1-CT) represent initiating steps in the epithelial-to-mesenchymal transition. Smoke provoked the rapid nuclear entry of p120ctn in complex with MUC1-CT that was inhibited using the MUC1-CT inhibitory peptides, PMIP and GO-201...
October 17, 2016: American Journal of Pathology
Xiaoting Gu, Chunxiao Lu, Dongxu He, Yangfan Lu, Jian Jin, Dequan Liu, Xin Ma
To define the role of the NOTCH signaling pathway in the development of chemoresistance and the associated epithelial-mesenchymal transition (EMT), we investigated the effect of Notch3 on adriamycin (ADM)-resistant human breast cancer cells (MCF-7/ADM cells). We found that Notch3 was downregulated and involved in the chemoresistance of MCF-7/ADM cells, while forced expression of Notch3 reversed the chemoresistance. Furthermore, fos-related antigen 1 (Fra1) was negatively regulated by Notch3 and was highly expressed in MCF-7/ADM cells...
October 14, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Jane Antony, Tuan Zea Tan, Zoe Kelly, Jeffrey Low, Mahesh Choolani, Chiara Recchi, Hani Gabra, Jean Paul Thiery, Ruby Yun-Ju Huang
Ovarian cancer is a complex disease with heterogeneity among the gene expression molecular subtypes (GEMS) between patients. Patients with tumors of a mesenchymal ("Mes") subtype have a poorer prognosis than patients with tumors of an epithelial ("Epi") subtype. We evaluated GEMS of ovarian cancer patients for molecular signaling profiles and assessed how the differences in these profiles could be leveraged to improve patient clinical outcome. Kinome enrichment analysis identified AXL as a particularly abundant kinase in Mes-subtype tumor tissue and cell lines...
October 4, 2016: Science Signaling
Cachétne S X Barrett, Ana C Millena, Shafiq A Khan
BACKGROUND: Activator Protein-1 (AP-1) family (cJun, JunB, JunD, cFos, FosB, Fra1, and Fra2) plays a central role in the transcriptional regulation of many genes that are associated with cell proliferation, differentiation, migration, metastasis, and survival. Many oncogenic signaling pathways converge at the AP-1 transcription complex. Transforming growth factor beta (TGF-β) is a multifunctional regulatory cytokine that regulates many aspects of cellular function, including cellular proliferation, differentiation, migration, apoptosis, adhesion, angiogenesis, immune surveillance, and survival...
September 7, 2016: Prostate
Alexandra Papoudou-Bai, Eleftheria Hatzimichael, Alexandra Barbouti, Panagiotis Kanavaros
The activator protein-1 (AP-1) is a dimeric transcription factor composed of proteins belonging to the Jun (c-Jun, JunB and JunD), Fos (c-Fos, FosB, Fra1 and Fra2) and activating transcription factor protein families. AP-1 is involved in various cellular events including differentiation, proliferation, survival and apoptosis. Deregulated expression of AP-1 transcription factors is implicated in the pathogenesis of various lymphomas such as classical Hodgkin lymphomas, anaplastic large cell lymphomas, diffuse large B cell lymphomas and adult T cell leukemia/lymphoma...
September 6, 2016: Clinical and Experimental Medicine
Antonio Giuliano, Rebecca Swift, Callum Arthurs, Georgina Marote, Francesca Abramo, Jenny McKay, Calum Thomson, Mariana Beltran, Michael Millar, Simon Priestnall, Jane Dobson, Fernando Costantino-Casas, Terry Petrou, Imelda M McGonnell, Anthony J Davies, Malcolm Weetman, Oliver A Garden, John R Masters, Christopher Thrasivoulou, Aamir Ahmed
Feline oral squamous cell carcinoma (FOSCC) is an aggressive neoplasm in cats. Little is known about the possible molecular mechanisms that may be involved in the initiation, maintenance and progression of FOSCC. Wnt signalling is critical in development and disease, including many mammalian cancers. In this study, we have investigated the expression of Wnt signalling related proteins using quantitative immunohistochemical techniques on tissue arrays. We constructed tissue arrays with 58 individual replicate tissue samples...
2016: PloS One
Byung-Jin Im, Sang Cheon Lee, Myung-Hyun Lee, Richard Leesungbok, Su-Jin Ahn, Yoon-Goo Kang, Do Yun Lee, Joon-Ho Yoon, Suk Won Lee
We demonstrate that a composite surface of microgroove titanium (Ti) with immobilized fibronectin (FN) or bone sialoprotein II (BSP2) promotes osteoblastic differentiation and osteogenic transcription factor expression in human bone marrow-derived mesenchymal stem cells (MSCs). Comparisons made between smooth microgrooves, microgrooves with silanization and microgrooves with matrix protein (FN or BSP2)-immobilization Ti surfaces revealed a significant promotion of in vitro osteogenic activity and osteoblastic differentiation at various timelines of culture...
2016: Biomedical Materials
Xiaoling Zhang, Joseph Wu, Suju Luo, Terry Lechler, Jennifer Y Zhang
FRA1 (Fos-like antigen 1) is highly expressed in many epithelial cancers including squamous cell carcinoma of the skin (cSCC) and head and neck (HNSCC). However, the functional importance and the mechanisms mediating FRA1 function in these cancers are not fully understood. Here, we demonstrate that FRA1 gene silencing in HNSCC and cSCC cells resulted in two consequences - impaired cell proliferation and migration. FRA1 regulation of cell growth was distinct from that of c-Jun, a prominent Jun group AP-1 factor...
June 7, 2016: Oncotarget
Eunice Yuen Ting Lau, Jessica Lo, Bowie Yik Ling Cheng, Mark Kin Fai Ma, Joyce Man Fong Lee, Johnson Kai Yu Ng, Stella Chai, Chi Ho Lin, Suk Ying Tsang, Stephanie Ma, Irene Oi Lin Ng, Terence Kin Wah Lee
Like normal stem cells, tumor-initiating cells (T-ICs) are regulated extrinsically within the tumor microenvironment. Because HCC develops primarily in the context of cirrhosis, in which there is an enrichment of activated fibroblasts, we hypothesized that cancer-associated fibroblasts (CAFs) would regulate liver T-ICs. We found that the presence of α-SMA(+) CAFs correlates with poor clinical outcome. CAF-derived HGF regulates liver T-ICs via activation of FRA1 in an Erk1,2-dependent manner. Further functional analysis identifies HEY1 as a direct downstream effector of FRA1...
May 10, 2016: Cell Reports
Jianguo Wu, Andrei I Ivanov, Paul B Fisher, Zheng Fu
Polo-like kinase 1 (PLK1) is a key cell cycle regulator implicated in the development of various cancers, including prostate cancer. However, the functions of PLK1 beyond cell cycle regulation remain poorly characterized. Here, we report that PLK1 overexpression in prostate epithelial cells triggers oncogenic transformation. It also results in dramatic transcriptional reprogramming of the cells, leading to epithelial-to-mesenchymal transition (EMT) and stimulation of cell migration and invasion. Consistently, PLK1 downregulation in metastatic prostate cancer cells enhances epithelial characteristics and inhibits cell motility...
2016: ELife
T Koehne, A Jeschke, F Petermann, S Seitz, M Neven, S Peters, J Luther, M Schweizer, T Schinke, B Kahl-Nieke, M Amling, J-P David
The ribosomal S6 kinase RSK2 is essential for osteoblast function, and inactivating mutations of RSK2 cause osteopenia in humans with Coffin-Lowry syndrome (CLS). Alveolar bone loss and premature tooth exfoliation are also consistently reported symptoms in CLS patients; however, the pathophysiologic mechanisms are unclear. Therefore, aiming to identify the functional relevance of Rsk2 for tooth development, we analyzed Rsk2-deficient mice. Here, we show that Rsk2 is a critical regulator of cementoblast function...
July 2016: Journal of Dental Research
Sung Keun Jung, Su Jeong Ha, Chang Hwa Jung, Yun Tai Kim, Hoo-Keun Lee, Myoung Ok Kim, Mee-Hyun Lee, Madhusoodanan Mottamal, Ann M Bode, Ki Won Lee, Zigang Dong
A number of natural phytochemicals have anti-photoaging properties that appear to be mediated through the inhibition of matrix metalloproteinase-1 (MMP-1) expression, but their direct target molecule(s) and mechanism(s) remain unclear. We investigated the effect of naringenin, a major flavonoid found in citrus, on UVB-induced MMP-1 expression and identified its direct target. The HaCaT human skin keratinocyte cell line and 3-dimensional (3-D) human skin equivalent cultures were treated or not treated with naringenin for 1 hr before exposure to UVB...
May 2016: Journal of Cellular and Molecular Medicine
Xiangfan Liu, Huapeng Li, Mihir Rajurkar, Qi Li, Jennifer L Cotton, Jianhong Ou, Lihua J Zhu, Hira L Goel, Arthur M Mercurio, Joo-Seop Park, Roger J Davis, Junhao Mao
The Tead family transcription factors are the major intracellular mediators of the Hippo-Yap pathway. Despite the importance of Hippo signaling in tumorigenesis, Tead-dependent downstream oncogenic programs and target genes in cancer cells remain poorly understood. Here, we characterize Tead4-mediated transcriptional networks in a diverse range of cancer cells, including neuroblastoma, colorectal, lung, and endometrial carcinomas. By intersecting genome-wide chromatin occupancy analyses of Tead4, JunD, and Fra1/2, we find that Tead4 cooperates with AP1 transcription factors to coordinate target gene transcription...
February 9, 2016: Cell Reports
Marzena Ciechomska, Steven O'Reilly, Stefan Przyborski, Fiona Oakley, Katarzyna Bogunia-Kubik, Jacob M van Laar
OBJECTIVE: To investigate whether epigenetic changes can modulate monocytes to produce tissue inhibitor of metalloproteinases 1 (TIMP-1) via Fra-2 (an activator protein 1 [AP-1] family member), a novel downstream mediator that promotes fibrogenesis. METHODS: AP-1 transcription factors and TIMP-1 expression were measured in monocytes from systemic sclerosis (SSc) patients and healthy controls. Involvement of Fra-2 in the regulation of TIMP-1 following treatment with Toll-like receptor 8 (TLR-8) agonist was investigated using a luciferase activity assay and chromatin immunoprecipitation (ChIP) analysis...
June 2016: Arthritis & Rheumatology
Ming-Wu Zheng, Chun-Hui Zhang, Kai Chen, Mei Huang, Ya-Ping Li, Wan-Ting Lin, Rong-Jie Zhang, Lei Zhong, Rong Xiang, Lin-Li Li, Xin-Yu Liu, Yu-Quan Wei, Sheng-Yong Yang
Triple-negative breast cancer (TNBC) is the most aggressive and deadly breast cancer subtype. To date, chemotherapy is the only systemic therapy and prognosis remains poor. Herein, we report the preclinical evaluation of SKLB646 in the treatment of TNBC; SKLB646 is a novel multiple kinase inhibitor developed by us recently. This compound potently inhibited SRC and VEGFR2 with IC50 values of 0.002 μmol/L and 0.012 μmol/L, respectively. It also considerably inhibited B-Raf and C-Raf with IC50 values of 0.022 and 0...
March 2016: Molecular Cancer Therapeutics
Dirk Mielenz, Bettina Grötsch, Jean-Pierre David
No abstract text is available yet for this article.
July 20, 2015: Oncotarget
Subbiah Rajasekaran, Chandramohan R Tamatam, Haranatha R Potteti, Venu Raman, Jae-Woo Lee, Michael A Matthay, Dolly Mehta, Narsa M Reddy, Sekhar P Reddy
Inappropriate lung inflammatory response following oxidant and toxicant exposure can lead to abnormal repair and disease pathogenesis, including fibrosis. Thus early detection of molecular and cellular processes and mediators promoting lung inflammation is necessary to develop better strategies for therapeutic intervention and disease management. Previously, we have shown that transcription factor Fra-1/AP-1 plays key roles in lung inflammatory response, as Fra-1-null mice are less susceptible than wild-type mice to LPS-induced lung injury and mortality...
August 15, 2015: American Journal of Physiology. Lung Cellular and Molecular Physiology
Deepa Subramanian, Wilawan Bunjobpol, Kanaga Sabapathy
Unlike p53, which is mutated at a high rate in human cancers, its homologue p73 is not mutated but is often overexpressed, suggesting a possible context-dependent role in growth promotion. Previously, we have shown that co-expression of TAp73 with the proto-oncogene c-Jun can augment cellular growth and potentiate transactivation of activator protein (AP)-1 target genes such as cyclin D1. Here, we provide further mechanistic insights into the cooperative activity between these two transcription factors. Our data show that TAp73-mediated AP-1 target gene transactivation relies on c-Jun dimerization and requires the canonical AP-1 sites on target gene promoters...
July 24, 2015: Journal of Biological Chemistry
Anna C Obenauf, Yilong Zou, Andrew L Ji, Sakari Vanharanta, Weiping Shu, Hubing Shi, Xiangju Kong, Marcus C Bosenberg, Thomas Wiesner, Neal Rosen, Roger S Lo, Joan Massagué
Drug resistance invariably limits the clinical efficacy of targeted therapy with kinase inhibitors against cancer. Here we show that targeted therapy with BRAF, ALK or EGFR kinase inhibitors induces a complex network of secreted signals in drug-stressed human and mouse melanoma and human lung adenocarcinoma cells. This therapy-induced secretome stimulates the outgrowth, dissemination and metastasis of drug-resistant cancer cell clones and supports the survival of drug-sensitive cancer cells, contributing to incomplete tumour regression...
April 16, 2015: Nature
Ramin Samadani, Jun Zhang, Amanda Brophy, Taiji Oashi, U Deva Priyakumar, E Prabhu Raman, Franz J St John, Kwan-Young Jung, Steven Fletcher, Edwin Pozharski, Alexander D MacKerell, Paul Shapiro
Constitutive activation of the extracellular-signal-regulated kinases 1 and 2 (ERK1/2) are central to regulating the proliferation and survival of many cancer cells. The current inhibitors of ERK1/2 target ATP binding or the catalytic site and are therefore limited in their utility for elucidating the complex biological roles of ERK1/2 through its phosphorylation and regulation of over 100 substrate proteins. To overcome this limitation, a combination of computational and experimental methods was used to identify low-molecular-mass inhibitors that are intended to target ERK1/2 substrate-docking domains and selectively interfere with ERK1/2 regulation of substrate proteins...
May 1, 2015: Biochemical Journal
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