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Tosol Yu, Bong Jun Cho, Eun Jung Choi, Ji Min Park, Dan Hyo Kim, In Ah Kim
Trastuzumab has been widely used for the treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, however, it cannot easily cross the blood-brain barrier (BBB) and is known to increase the incidence of brain metastases. In contrast, lapatinib has a low molecular weight and can cross the BBB and it could be useful to treat brain metastases in patients with HER2-positive breast cancer.To explore the impact of lapatinib on radiation response, we conducted an in vitro experiment using SKBR3 and BT474 breast carcinoma cells exhibiting HER2/neu amplification...
October 12, 2016: Oncotarget
Jia You, Jia Liu, Yantao Bao, Liqun Wang, Yang Yu, Lei Wang, Di Wu, Chang Liu, Nan Wang, Fei Wang, Falin Wang, Lu Xu, Xing Tian, Hongbin Liang, Yating Gao, Rongwei Guan, Jing Bai, Xiangning Meng, Wenjing Sun, Xin-Yuan Guan, Chunyu Zhang, Songbin Fu, Yan Jin
Previous studies have shown that the oncogene SEI1 is highly expressed in ovarian carcinomas, and promoting genomic instability. However, the molecular mechanism of SEI1 in promoting genomic instability remains unclear. We observed SEI1 overexpression in 30 of 46 cases of ovarian cancer compared to non-tumor tissues and the overexpression of SEI1 was positively associated with the tumor FIGO stage. Our functional studies revealed that overexpression of SEI1 could induce genomic instability and increased DNA strand breaks...
January 28, 2017: Cancer Letters
Samir Gupta, Han Sun, Sang Yi, Joy Storm, Guanghua Xiao, Bijal A Balasubramanian, Song Zhang, Raheela Ashfaq, Don C Rockey
Risk stratification using number, size, and histology of colorectal adenomas is currently suboptimal for identifying patients at increased risk for future colorectal cancer. We hypothesized that molecular markers of carcinogenesis in adenomas, measured via immunohistochemistry, may help identify high-risk patients. To test this hypothesis, we conducted a retrospective, 1:1 matched case-control study (n = 216; 46% female) in which cases were patients with colorectal cancer and synchronous adenoma and controls were patients with adenoma but no colorectal cancer at baseline or within 5 years of follow-up...
October 2014: Cancer Prevention Research
B C Nair, S R Krishnan, G R Sareddy, M Mann, B Xu, M Natarajan, P Hasty, D Brann, R R Tekmal, R K Vadlamudi
Proline-, glutamic acid- and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions...
September 2014: Cell Death and Differentiation
Gianmaria Liccardi, John A Hartley, Daniel Hochhauser
PURPOSE: The epidermal growth factor receptor (EGFR) plays an important role in cellular response to chemotherapy and radiotherapy through modulation of DNA repair. EGFR activates DNA-dependent protein kinase (DNA-PK) stimulating repair of DNA strand breaks (SB) and interstrand crosslinks (ICL). We investigated the role of EGFR in repair of ionizing radiation (IR)-induced SB independently of DNA-PK. EXPERIMENTAL DESIGN: The EGFR interactome was investigated via mass spectrometry...
July 1, 2014: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Jonathan F Goodwin, Matthew J Schiewer, Jeffry L Dean, Randy S Schrecengost, Renée de Leeuw, Sumin Han, Teng Ma, Robert B Den, Adam P Dicker, Felix Y Feng, Karen E Knudsen
UNLABELLED: Alterations in DNA repair promote tumor development, but the impact on tumor progression is poorly understood. Here, discovery of a biochemical circuit linking hormone signaling to DNA repair and therapeutic resistance is reported. Findings show that androgen receptor (AR) activity is induced by DNA damage and promotes expression and activation of a gene expression program governing DNA repair. Subsequent investigation revealed that activated AR promotes resolution of double-strand breaks and resistance to DNA damage both in vitro and in vivo...
November 2013: Cancer Discovery
Tibor Pankotai, Céline Bonhomme, David Chen, Evi Soutoglou
DNA double-strand break (DSB) repair interferes with ongoing cellular processes, including replication and transcription. Although the process of replication stalling upon collision of replication forks with damaged DNA has been extensively studied, the fate of elongating RNA polymerase II (RNAPII) that encounters a DSB is not well understood. We show that the occurrence of a single DSB at a human RNAPII-transcribed gene leads to inhibition of transcription elongation and reinitiation. Upon inhibition of DNA protein kinase (DNAPK), RNAPII bypasses the break and continues transcription elongation, suggesting that it is not the break per se that inhibits the processivity of RNAPII, but the activity of DNAPK...
February 12, 2012: Nature Structural & Molecular Biology
Kiran Mahajan, Nupam P Mahajan
AKT/PKB serine threonine kinase, a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers. Although phosphatidylinositol-3-OH kinase (PI3K), a lipid kinase, is well characterized as a major regulator of AKT activation in response to a variety of ligands, recent studies highlight a diverse group of tyrosine (Ack1/TNK2, Src, PTK6) and serine/threonine (TBK1, IKBKE, DNAPKcs) kinases that activate AKT directly to promote its pro-proliferative signaling functions...
September 2012: Journal of Cellular Physiology
Marta Viana-Pereira, Alicia Lee, Sergey Popov, Dorine A Bax, Safa Al-Sarraj, Leslie R Bridges, João N Stávale, Darren Hargrave, Chris Jones, Rui M Reis
High grade gliomas (HGG) are one of the leading causes of cancer-related deaths in children, and there is increasing evidence that pediatric HGG may harbor distinct molecular characteristics compared to adult tumors. We have sought to clarify the role of microsatellite instability (MSI) in pediatric versus adult HGG. MSI status was determined in 144 patients (71 pediatric and 73 adults) using a well established panel of five quasimonomorphic mononucleotide repeat markers. Expression of MLH1, MSH2, MSH6 and PMS2 was determined by immunohistochemistry, MLH1 was assessed for mutations by direct sequencing and promoter methylation using MS-PCR...
2011: PloS One
Guang-Hui Liu, Basam Z Barkho, Sergio Ruiz, Dinh Diep, Jing Qu, Sheng-Lian Yang, Athanasia D Panopoulos, Keiichiro Suzuki, Leo Kurian, Christopher Walsh, James Thompson, Stephanie Boue, Ho Lim Fung, Ignacio Sancho-Martinez, Kun Zhang, John Yates, Juan Carlos Izpisua Belmonte
Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature ageing disease, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs). HGPS is caused by a single point mutation in the lamin A (LMNA) gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various ageing-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS...
April 14, 2011: Nature
Cristina Bilbao, Raquel Ramírez, Germán Rodríguez, Orlando Falcón, Laureano León, Nicolás Díaz-Chico, Manuel Perucho, Juan Carlos Díaz-Chico
AIM: DNA double strand break (DSB) repair is a central cellular mechanism of the DNA damage response to maintain genomic stability. DSB components are frequently mutated in colorectal cancer with microsatellite instability (MSI). We investigated whether DSB repair is involved in endometrial cancer (EC) with MSI. METHODS: Mononucleotide microsatellite tracts of 14 genes of the DSB repair system were analysed in a series of 41 EC with MSI. Among these genes, the microcephalin 1 (MCPH1/BRIT1) has never been tested as target of MSI in tumour series...
October 2010: European Journal of Cancer
Jia Liu, Alokes Majumdar, Jilan Liu, Lawrence H Thompson, Michael M Seidman
Double strand breaks (DSBs) can be repaired by homology independent nonhomologous end joining (NHEJ) pathways involving proteins such as Ku70/80, DNAPKcs, Xrcc4/Ligase 4, and the Mre11/Rad50/Nbs1 (MRN) complex. DSBs can also be repaired by homology-dependent pathways (HDR), in which the MRN and CtIP nucleases produce single strand ends that engage homologous sequences either by strand invasion or strand annealing. The entry of ends into HDR pathways underlies protocols for genomic manipulation that combine site-specific DSBs with appropriate informational donors...
July 23, 2010: Journal of Biological Chemistry
Shyam Daya, Nenita Cortez, Kenneth I Berns
Adeno-associated virus type 2 (AAV 2) is the only eukaryotic virus capable of site-specific integration; the target site is at chromosome 19q13.4, a site termed AAVS1. The biology of AAV latency has been extensively studied in cell culture, yet the precise mechanism and the required cellular factors are not known. In this study, we assessed the relative frequencies of stable site-specific integration by characterization of cell clones containing integrated AAV vectors. By this assay, two proteins involved in nonhomologous end joining (NHEJ), DNAPKcs and ligase IV, exhibit differential effects on AAV site-specific integration...
November 2009: Journal of Virology
A P Kouzmenko, K Takeyama, Y Kawasaki, T Akiyama, S Kato
The adenomatous polyposis coli (APC) is a tumor suppressor whose loss of function leads to colon cancer. APC shuttles between the nucleus and cytoplasm, however its role in the nucleus remains elusive. We have found that nuclear APC specifically associates with transcriptionally active chromatin through structural elements located downstream to the region of frequent truncation mutations found in colorectal tumors. We show that a recombinant APC fragment comprising such elements associates in vivo with euchromatin and preferentially binds in vitro to acetylated histone H3...
August 21, 2008: Oncogene
Tanya R Da Sylva, Ivan C Fong, Lesley A Cunningham, Gillian E Wu
The expression of RAG1 and RAG2 is essential for V(D)J rearrangement of the immunoglobulin (Ig) locus in developing B cells. In mature B cells further V(D)J rearrangement is suppressed and RAG1/2 proteins decline to undetectable levels. However, there is evidence that mature B cells in the periphery may re-express RAG1/2. In humans evidence of RAG1/2 re-expression is often linked with an autoimmune state, indicating that further understanding of re-expression may be crucial to understanding immune disorders...
February 2007: Molecular Immunology
Franca Majone, Roberto Luisetto, Daniela Zamboni, Yoichi Iwanaga, Kuan-Teh Jeang
The HTLV-1 Tax oncoprotein rapidly induces cytogenetic damage which can be measured by a significant increase in the number of micronuclei (MN) in cells. Tax is thought to have both aneuploidogenic and clastogenic effects. To examine the cellular target for Tax which might mechanistically explain the clastogenic phenomenon, we tested the ability of Tax to induce MN in rodents cells genetically defective for either the Ku80 protein or the catalytic subunit of DNA protein kinase (DNAPKcs). We found that cells genetically mutated in Ku80 were refractory to Tax's induction of MN while cells knocked-out for DNAPKcs showed increased number of Tax-induced MN...
July 13, 2005: Retrovirology
C Alapetite
Some rare hereditary syndromes demonstrate high cancer risk and hypersensitivity in response to exposures to agents such as ultraviolet or ionising radiation, and are characterised by a defective processing of DNA damage. They highlight the importance of the individual capacity of restoring the genomic integrity in the individual risk associated to exposures. The comet assay, a simple technique that detects DNA strand breaks, requires few cells and allows examination of DNA repair capacities in established cell lines, in blood samples or biopsies...
September 1998: Cancer Radiothérapie: Journal de la Société Française de Radiothérapie Oncologique
M Fujimoto, N Matsumoto, T Tsujita, H Tomita, S Kondo, N Miyake, M Nakano, N Niikawa
The gene, DNAPKcs (XRCC7), for the human DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a strong candidate that complements a severe combined immunodeficiency (scid) and hypersensitivity to ionizing radiation in mice. We constructed a cosmid library from a previously identified, X RCC7-covering YAC clone (943G4). From the library, we isolated three cosmid clones containing the 5'-region of XRCC7. Sequence analysis with primer walking on a 6.3-kb segment of these cosmids identified the promoter region, the first ten exons and nine intron-exon boundaries of XRCC7...
April 28, 1997: DNA Research: An International Journal for Rapid Publication of Reports on Genes and Genomes
A M Carr
The Mec1(sc)/Rad3(sp) protein family is central to the checkpoint pathways of cells. Functions upstream and downstream of Mec1(sc)/Rad3(sp) show both similarities and differences when compared between organisms. Analogy with a related protein, DNAPKcs, suggests that different subunits may activate Mec1(sc)/Rad3(sp) in response to specific DNA or DNA-protein structures.
February 1997: Current Opinion in Genetics & Development
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