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Miranda Grace, Karl Munger
Gamma HPV197 was the most frequently identified HPV when human skin cancer specimens were analyzed by deep sequencing (Arroyo Muhr et al., Int. J. Cancer 136: 2546-55, 2015). To gain insight into the biological activities of HPV197, we investigated the cellular interactomes of HPV197 E6 and E7. HPV197 E6 protein interacts with a broad spectrum of cellular LXXLL domain proteins, including UBE3A and MAML1. HPV197 E6 also binds and inhibits the TP53 tumor suppressor and interacts with the CCR4-NOT ubiquitin ligase and deadenylation complex...
October 20, 2016: Virology
Lu Chen, Courtney A Kurtyka, Eric A Welsh, Jason I Rivera, Brienne E Engel, Teresita Muñoz-Antonia, Sean J Yoder, Steven A Eschrich, Ben C Creelan, Alberto A Chiappori, Jhanelle E Gray, Jose Luis Ramirez, Rafael Rosell, Matthew B Schabath, Eric B Haura, Dung-Tsa Chen, W Douglas Cress
Clinicians routinely prescribe adjuvant chemotherapy (ACT) for resected non-small cell lung cancer patients. However, ACT only improves five-year disease-free survival in stage I-III non-small cell lung cancer by 5-15%, with most patients deriving no benefit. Herein, deregulation of the E2F pathway was explored as a biomarker in lung adenocarcinoma patients. An E2F pathway scoring system, based on 74 E2F-regulated genes, was trained for RNA from two platforms: fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissues...
October 14, 2016: Oncotarget
Jenny Hsu, Julien Sage
The E2F family of transcription factors is a key determinant of cell proliferation in response to extra- and intra-cellular signals. Within this family, E2F4 is a transcriptional repressor whose activity is critical to engage and maintain cell cycle arrest in G0/G1 in conjunction with members of the retinoblastoma (RB) family. However, recent observations challenge this paradigm and indicate that E2F4 has a multitude of functions in cells besides this cell cycle regulatory role, including in embryonic and adult stem cells, during regenerative processes, and in cancer...
October 18, 2016: Cell Cycle
Hsiang-Tsui Wang, Tzu-Ying Chen, Ching-Wen Weng, Chun-Hsiang Yang, Moon-Shong Tang
Acrolein (Acr) is a potent cytotoxic and DNA damaging agent which is ubiquitous in the environment and abundant in tobacco smoke. Acr is also an active cytotoxic metabolite of the anti-cancer drugs cyclophosphamide and ifosfamide. The mechanisms via which Acr exerts its anti-cancer activity and cytotoxicity are not clear. In this study, we found that Acr induces cytotoxicity and cell death in human cancer cells with different activities of p53. Acr preferentially binds nucleolar ribosomal DNA (rDNA) to form Acr-deoxyguanosine adducts, and induces oxidative damage to both rDNA and ribosomal RNA (rRNA)...
October 12, 2016: Oncotarget
Clotilde Costa, Mirentxu Santos, Mónica Martínez-Fernández, Corina Lorz, Sara Lázaro, Jesús M Paramio
E2F/RB activity is altered in most human tumors. The retinoblastoma family of proteins plays a key role in regulating the progression of the cell cycle from the G1 to S phases. This is achieved through negative regulation of E2F transcription factors, important positive regulators of cell cycle entry. E2F family members are divided into two groups: activators (E2F1-E2F3a) and repressors (E2F3b-E2F8). E2F4 accounts for a large part of the E2F activity and is a main E2F repressor member in vivo. Perturbations in the balance from quiescence towards proliferation contribute to increased mitotic gene expression levels frequently observed in cancer...
September 30, 2016: Oncotarget
Hao Yang, Xiaoping Zhao, Li Zhao, Liu Liu, Jiajin Li, Wenzhi Jia, Jianjun Liu, Gang Huang
Although cancer cells are known to be "addicted" to glucose, the effect of glucose in proliferation of these cells remains elusive. Here, we report that upon glucose induction, protein arginine methyltransferase 5 (PRMT5) exerts a profound effect on the G1-S cell cycle progression via directly interacting with cyclin dependent kinase 4 (CDK4) in hepatocellular carcinoma (HCC). Upregulation of both PRMT5 and CDK4 predicts more malignant characteristics in human HCC tissues. Mechanistically, glucose promotes the interaction between PRMT5 and CDK4, which leads to activation of CDK4-RB-E2F-mediated transcription via releasing CDKN2A from CDK4...
September 30, 2016: Oncotarget
Lin-Hai Yan, Zhi-Ning Chen, Li Li, Jia Chen, Xian-Wei Mo, Yu-Zhou Qin, Wen-E Wei, Hai-Quan Qin, Yuan Lin, Jian-Si Chen
Activation of the transcription factor E2F-1 gene is a negative event in dendritic cell (DC) maturation process. Down-regulation of E2F1 causes immaturity of DC thereby stopping antigen production which in turn leads to inhibition of immune responses. E2F-1-free stimulates the NF-kB signaling pathway, leading to activation of monocytes and several other transcription factor genes. In the study, we report that down-regulation of E2F-1 in DCs promote anti-tumor immune response in gastric cancer (GC) cells through a novel mechanism...
October 4, 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Gunnar Wichmann
The human papillomavirus (HPV) comprises a heterogeneous group of double-strand DNA viruses with variable potential to infect human epithelial cells and trigger neoplastic transformation. Its 8 kb genome encodes proteins required for virus replication and self-organized formation of infectious particles but also for early proteins E6 and E7 able to trigger neoplastic transformation. E6 and E7 of high-risk (HR) HPV subtypes can bind to p53 or release E2F and abrogate replication control. Due to variable amino acid sequence (AAS) in the binding sites of E6 and E7 particular HR-HPV variants within subtypes are essentially heterogeneous in efficacy triggering neoplastic transformation and cancer development...
2017: Recent Results in Cancer Research
Renato José Mendonça Natalino, Célia Beatriz Gianotti Antoneli, Karina de Cássia Braga Ribeiro, Antônio Hugo José Fróes Marques Campos, Fernando Augusto Soares
Retinoblastoma is the most common intraocular malignant neoplasia during childhood and results from the partial or total inactivity of the retinoblastoma protein (pRb). In the absence of pRb, the E2F transcription factors increase the levels of cell cycle proteins as well as some pro-apoptotic proteins. We intended to study the immunohistochemistry profile of apoptotic-related proteins in retinoblastoma. We also evaluated the association between the expression of apoptotic protein and stage of tumor or survivor after a 5year follow up...
September 22, 2016: Pathology, Research and Practice
Amir Pozner, Tommy W Terooatea, Bethany A Buck-Koehntop
The correlation between aberrant DNA methylation with cancer promotion and progression has prompted an interest in discerning the associated regulatory mechanisms. Kaiso (ZBTB33) is a specialized transcription factor that selectively recognizes methylated CpG-containing sites as well as a sequence-specific DNA target. Increasing reports link ZBTB33 overexpression and transcriptional activities with metastatic potential and poor prognosis in cancer, though there is little mechanistic insight into how cells harness ZBTB33 transcriptional capabilities to promote and progress disease...
September 30, 2016: Journal of Biological Chemistry
Jian Li, Laetitia Chauve, Grace Phelps, Renée M Brielmann, Richard I Morimoto
Heat-shock factor (HSF) is the master transcriptional regulator of the heat-shock response (HSR) and is essential for stress resilience. HSF is also required for metazoan development; however, its function and regulation in this process are poorly understood. Here, we characterize the genomic distribution and transcriptional activity of Caenorhabditis elegans HSF-1 during larval development and show that the developmental HSF-1 transcriptional program is distinct from the HSR. HSF-1 developmental activation requires binding of E2F/DP to a GC-rich motif that facilitates HSF-1 binding to a heat-shock element (HSE) that is degenerate from the consensus HSE sequence and adjacent to the E2F-binding site at promoters...
September 29, 2016: Genes & Development
Lin-Hai Yan, Zhi-Ning Chen, Li-Li, Jia Chen, Wen-E Wei, Xian-Wei Mo, Yu-Zhou Qin, Yuan Lin, Jian-Si Chen
Resistance to oxaliplatin (OXA)-based chemotherapy regimens continues to be a major cause of gastric cancer (GC) recurrence and metastasis. We analyzed GC samples and matched non-tumorous control stomach tissues from 280 patients and found that miR-135a was overexpressed in GC samples relative to control tissues. Tumors with high miR-135a expression were more likely to have aggressive characteristics (high levels of carcino-embryonic antigen, vascular invasion, lymphatic metastasis, and poor differentiation) than those with low levels...
September 23, 2016: Oncotarget
Ying Yuan, Erich M Sturgis, Lijun Zhu, Meixia Lu, Yuncheng Li, Qingyi Wei, Guojun Li
Human papillomavirus (HPV) activates E2F1-driven transcription via the E7-RB1-E2F pathway. Genetic polymorphisms in the 3' untranslated region (UTR) targeted by miRNAs can affect the regulation of target genes and individual cancer risk. Thus, we hypothesized that a polymorphism at the 3'UTR miRNA binding site of E2F1 gene (rs3213180) was associated with risk of oral squamous cell carcinoma (OSCC) and tumor HPV status of oropharynx squamous cell carcinoma (OPSCC). We determined the E2F1rs3213180 polymorphism and HPV16 L1 serology of 325 OSCC patients and 335 controls, and tumor HPV16 status of 552 OPSCC...
September 28, 2016: Molecular Carcinogenesis
Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M Hoffman
Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam® histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam® grew into tumor-like structures with G0/G1 cancer cells in the center and S/G2 cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively...
2016: PloS One
Wei Zhu, Liang Ye, Jianzhao Zhang, Pengfei Yu, Hongbo Wang, Zuguang Ye, Jingwei Tian
PFKFB3 (6-phosphofructo-2-kinase) synthesizes fructose 2,6-bisphosphate (F2,6P2), which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. Overexpression of the PFKFB3 enzyme leads to high glycolytic metabolism, which is required for cancer cells to survive in the harsh tumor microenvironment. The objective of this study was to investigate the antitumor activity of PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), a small molecule inhibitor of PFKFB3, against gastric cancer and to explore its potential mechanisms...
2016: PloS One
Hai Ha Thi Pham, Yeong-Ae Seong, Chul-Woong Oh, Gun-Do Kim
Cyperus amuricus (C. amuricus) is one of the most common herbs in Oriental folk medicine for exerting astringent, diuretic, wound healing and other intestinal problems. However, little is known about the molecular mechanism of C. amuricus on anticancer activity. In the present study, the underlying mechanism of the anticancer effect of C. amuricus were elucidated. The methyl alcohol extract from the whole plant of C. amuricus exhibited cytotoxicity against Hep3B cells, but not against A549 and HaCaT cells...
September 20, 2016: International Journal of Oncology
Albert Gubern, Manel Joaquin, Miriam Marquès, Pedro Maseres, Javier Garcia-Garcia, Ramon Amat, Daniel González-Nuñez, Baldo Oliva, Francisco X Real, Eulàlia de Nadal, Francesc Posas
Control of the G1/S phase transition by the Retinoblastoma (RB) tumor suppressor is critical for the proliferation of normal cells in tissues, and its inactivation is one of the most fundamental events leading to cancer. Cyclin-dependent kinase (CDK) phosphorylation inactivates RB to promote cell cycle-regulated gene expression. Here we show that, upon stress, the p38 stress-activated protein kinase (SAPK) maximizes cell survival by downregulating E2F gene expression through the targeting of RB. RB undergoes selective phosphorylation by p38 in its N terminus; these phosphorylations render RB insensitive to the inactivation by CDKs...
October 6, 2016: Molecular Cell
Ricardo C H Del Rosario, Joseph Ray Clarence G Damasco, Baltazar D Aguda
The restriction point marks a switch in G1 from growth factor-dependent to growth factor-independent progression of the cell cycle. The proper regulation of this switch is important for normal cell processes; aberrations could result in a number of diseases such as cancer, neurodegenerative disorders, stroke and myocardial infarction. To further understand the regulation of the restriction point, we extended a mathematical model of the Rb-E2F pathway to include members of the microRNA cluster miR-17-92. Our mathematical analysis shows that microRNAs play an essential role in fine-tuning and providing robustness to the switch...
2016: Scientific Reports
Jinshan Zhao, Hegang Li, Kaidong Liu, Baoxun Zhang, Peipei Li, Jianning He, Ming Cheng, Wei De, Jifeng Liu, Yaofeng Zhao, Lihua Yang, Nan Liu
Goats are an important source of fibers. In the present study microarray technology was used to investigate the potential genes primarily involved in hair and cashmere growth in the Laiwu black goat. A total of 655 genes differentially expressed in body (hair‑growing) and groin (hairless) skin were identified, and their potential association with hair and cashmere growth was analyzed. The majority of genes associated with hair growth regulation could be assigned to intracellular, intracellular organelle, membrane‑bound vesicle, cytoplasmic vesicle, pattern binding, heparin binding, polysaccharide binding, glycosaminoglycan binding and cytoplasmic membrane‑bound vesicle categories...
October 2016: Molecular Medicine Reports
Chris R Evelyn, Erika M Lisabeth, Susan M Wade, Andrew J Haak, Craig N Johnson, Elizabeth R Lawlor, Richard R Neubig
Metastasis is the major cause of cancer deaths and control of gene transcription has emerged as a critical contributing factor. RhoA- and RhoC-induced gene transcription via the actin-regulated transcriptional co-activator megakaryocytic leukemia (MKL) and serum response factor (SRF) drive metastasis in breast cancer and melanoma. We recently identified a compound, CCG-1423, which blocks Rho/MKL/SRF-mediated transcription and inhibits PC-3 prostate cancer cell invasion. Here, we undertook a genome-wide expression study in PC-3 cells to explore the mechanism and function of this compound...
2016: Microarrays
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