7 results on '"Saria EA"'
Search Results
2. Kinase-independent role of cyclin D1 in chromosomal instability and mammary tumorigenesis.
- Author
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Casimiro MC, Di Sante G, Crosariol M, Loro E, Dampier W, Ertel A, Yu Z, Saria EA, Papanikolaou A, Li Z, Wang C, Addya S, Lisanti MP, Fortina P, Cardiff RD, Tozeren A, Knudsen ES, Arnold A, and Pestell RG
- Subjects
- Amino Acid Substitution, Aneuploidy, Animals, Catalytic Domain genetics, Cell Transformation, Neoplastic genetics, Cells, Cultured, Centrosome ultrastructure, Chromosomal Instability genetics, Cyclin D1 deficiency, Cyclin D1 genetics, Female, Fibroblasts, Genes, bcl-1, Humans, Mammary Tumor Virus, Mouse physiology, Mice, Mice, Knockout, Mice, Transgenic, Mutation, Piperazines pharmacology, Pyridines pharmacology, Recombinant Fusion Proteins metabolism, Spindle Apparatus ultrastructure, Transduction, Genetic, Adenocarcinoma genetics, Cyclin D1 physiology, Mammary Neoplasms, Experimental genetics
- Abstract
Cyclin D1 is an important molecular driver of human breast cancer but better understanding of its oncogenic mechanisms is needed, especially to enhance efforts in targeted therapeutics. Currently, pharmaceutical initiatives to inhibit cyclin D1 are focused on the catalytic component since the transforming capacity is thought to reside in the cyclin D1/CDK activity. We initiated the following study to directly test the oncogenic potential of catalytically inactive cyclin D1 in an in vivo mouse model that is relevant to breast cancer. Herein, transduction of cyclin D1(-/-) mouse embryonic fibroblasts (MEFs) with the kinase dead KE mutant of cyclin D1 led to aneuploidy, abnormalities in mitotic spindle formation, autosome amplification, and chromosomal instability (CIN) by gene expression profiling. Acute transgenic expression of either cyclin D1(WT) or cyclin D1(KE) in the mammary gland was sufficient to induce a high CIN score within 7 days. Sustained expression of cyclin D1(KE) induced mammary adenocarcinoma with similar kinetics to that of the wild-type cyclin D1. ChIP-Seq studies demonstrated recruitment of cyclin D1(WT) and cyclin D1(KE) to the genes governing CIN. We conclude that the CDK-activating function of cyclin D1 is not necessary to induce either chromosomal instability or mammary tumorigenesis.
- Published
- 2015
- Full Text
- View/download PDF
3. ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice.
- Author
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Casimiro MC, Crosariol M, Loro E, Ertel A, Yu Z, Dampier W, Saria EA, Papanikolaou A, Stanek TJ, Li Z, Wang C, Fortina P, Addya S, Tozeren A, Knudsen ES, Arnold A, and Pestell RG
- Subjects
- Animals, Binding Sites, Breast Neoplasms genetics, Cell Line, Tumor, Chromatin Immunoprecipitation, Chromosome Aberrations, Female, Fibroblasts metabolism, Gene Expression Regulation, Neoplastic, Genome-Wide Association Study, Humans, Karyotyping, Mice, Mice, Transgenic, Transcription, Genetic, Chromosomal Instability, Cyclin D1 genetics
- Abstract
Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1(-/-) mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNA-bound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1-rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland-targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability.
- Published
- 2012
- Full Text
- View/download PDF
4. Tissue-specific regulatory regions of the PTH gene localized by novel chromosome 11 rearrangement breakpoints in a parathyroid adenoma.
- Author
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Mallya SM, Wu HI, Saria EA, Corrado KR, and Arnold A
- Subjects
- Alleles, Binding Sites, Conserved Sequence genetics, Cyclin D1 genetics, Cyclin D1 metabolism, Gene Expression Regulation, Neoplastic, Genetic Loci genetics, Humans, In Situ Hybridization, Fluorescence, Interphase, Male, Organ Specificity genetics, Reverse Transcriptase Polymerase Chain Reaction, Species Specificity, Transcription Factors, Chromosome Breakpoints, Chromosomes, Human, Pair 11 genetics, Gene Rearrangement genetics, Parathyroid Hormone genetics, Parathyroid Neoplasms genetics, Regulatory Sequences, Nucleic Acid genetics
- Abstract
Parathyroid adenomas can contain clonal rearrangements of chromosome 11 that activate the cyclin D1 oncogene through juxtaposition with the PTH gene. Here we describe such a chromosomal rearrangement whose novel features provide clues to locating elusive cis-regulatory elements in the PTH gene and also expand the physical spectrum of pathogenetic breakpoints in the cyclin D1 gene region. Southern blot analyses of the parathyroid adenoma revealed rearrangement in the PTH gene locus. Analysis of rearranged DNA clones that contained the breakpoint, obtained by screening a tumor genomic library, pinpointed the breakpoint in the PTH locus 3.3 kb upstream of the first exon. Accordingly, highly conserved distal elements of the PTH 5' regulatory region were rearranged at the breakpoint approximately 450 kb upstream of the cyclin D1 oncogene, resulting in overexpression of cyclin D1 mRNA. Thus, PTH-cyclin D1 gene rearrangement breakpoints in parathyroid tumors can be located far from those previously recognized. In addition to expanding the molecular spectrum of pathogenetic chromosomal lesions in this disease, features of this specific rearrangement reinforce the existence of one or more novel cis-enhancer/regulatory elements for PTH gene expression and narrow their location to a 1.7-kb DNA segment in the distal PTH promoter., (Copyright © 2010 American Society for Bone and Mineral Research.)
- Published
- 2010
- Full Text
- View/download PDF
5. Somatic mutations in SQSTM1 detected in affected tissues from patients with sporadic Paget's disease of bone.
- Author
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Merchant A, Smielewska M, Patel N, Akunowicz JD, Saria EA, Delaney JD, Leach RJ, Seton M, and Hansen MF
- Subjects
- Adolescent, Alleles, Base Sequence, Bone and Bones metabolism, Case-Control Studies, DNA Mutational Analysis, Exons genetics, Gene Expression Regulation, Neoplastic, Humans, Microdissection, Molecular Sequence Data, Osteitis Deformans blood, Osteitis Deformans complications, Osteitis Deformans pathology, Osteosarcoma complications, Osteosarcoma genetics, Osteosarcoma pathology, Sequestosome-1 Protein, Viral Proteins, Adaptor Proteins, Signal Transducing genetics, Bone and Bones pathology, Mutation genetics, Osteitis Deformans genetics
- Abstract
Paget's disease of bone (PDB) is a focal disorder of bone remodeling that leads to overgrowth of affected bone, with rare progression to osteosarcoma. Extensive studies of familial PDB showed that a majority of cases harbor germline mutations in the Sequestosome1 gene (SQSTM1). In contrast, little is known about the mutational status of SQSTM1 in sporadic PDB. We hypothesized that somatic SQSTM1 mutations might occur in the affected tissues of sporadic PDB and pagetic osteosarcoma. We used laser capture microdissection to capture homogeneous populations of cells from the affected bone or tumor of patients with sporadic PDB or pagetic osteosarcoma, respectively. DNA from these samples and appropriate controls was used for sequence analysis and allelic discrimination analysis. Two of five patients with sporadic PDB had SQSTM1(C1215T) mutations detected in their affected bone but not in their blood samples, indicating a somatic origin of the mutations. Samples from three of five sporadic pagetic osteosarcoma patients had the SQSTM1(C1215T) mutation, whereas the normal adjacent tissue from two of these tumors clearly lacked the mutation, again indicating an occurrence of somatic events. No SQSTM1 mutations were found in primary adolescent osteosarcomas. The discovery of somatic SQSTM1 mutations in sporadic PDB and pagetic osteosarcoma shows a role for SQSTM1 in both sporadic and inherited PDB. The discovery of somatically acquired mutations in both the diseased bone and tumor samples suggests a paradigm shift in our understanding of this disease.
- Published
- 2009
- Full Text
- View/download PDF
6. PHC3, a component of the hPRC-H complex, associates with E2F6 during G0 and is lost in osteosarcoma tumors.
- Author
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Deshpande AM, Akunowicz JD, Reveles XT, Patel BB, Saria EA, Gorlick RG, Naylor SL, Leach RJ, and Hansen MF
- Subjects
- Base Sequence, DNA, DNA-Binding Proteins genetics, Humans, Loss of Heterozygosity, Nuclear Proteins, Polycomb Repressive Complex 1, Protein Binding, Tumor Cells, Cultured, DNA-Binding Proteins metabolism, E2F6 Transcription Factor metabolism, Osteosarcoma metabolism, Resting Phase, Cell Cycle
- Abstract
Polyhomeotic-like 3 (PHC3) is a ubiquitously expressed member of the polycomb gene family and part of the human polycomb complex hPRC-H. We found that in normal cells PHC3 associated with both hPRC-H complex components and with the transcription factor E2F6. In differentiating and confluent cells, PHC3 and E2F6 showed nuclear colocalization in a punctate pattern that resembled the binding of polycomb bodies to heterochromatin. This punctate pattern was not seen in proliferating cells suggesting that PHC3 may be part of an E2F6-polycomb complex that has been shown to occupy and silence target promoters in G(0). Previous loss of heterozygosity (LoH) analyses had shown that the region containing PHC3 underwent frequent LoH in primary human osteosarcoma tumors. When we examined normal bone and human osteosarcoma tumors, we found loss of PHC3 expression in 36 of 56 osteosarcoma tumors. Sequence analysis revealed that PHC3 was mutated in nine of 15 primary osteosarcoma tumors. These findings suggest that loss of PHC3 may favor tumorigenesis by potentially disrupting the ability of cells to remain in G(0).
- Published
- 2007
- Full Text
- View/download PDF
7. Cyclooxygenase-2 is up-regulated in proliferative inflammatory atrophy of the prostate, but not in prostate carcinoma.
- Author
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Zha S, Gage WR, Sauvageot J, Saria EA, Putzi MJ, Ewing CM, Faith DA, Nelson WG, De Marzo AM, and Isaacs WB
- Subjects
- Atrophy enzymology, Blotting, Western, Cyclooxygenase 2, Disease Progression, Epithelium enzymology, Epithelium pathology, Humans, Immunohistochemistry, Isoenzymes genetics, Male, Membrane Proteins, Prostaglandin-Endoperoxide Synthases genetics, Prostatic Neoplasms genetics, Prostatic Neoplasms pathology, RNA, Messenger biosynthesis, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Stromal Cells enzymology, Stromal Cells pathology, Tumor Cells, Cultured, Up-Regulation, Isoenzymes biosynthesis, Prostaglandin-Endoperoxide Synthases biosynthesis, Prostate pathology, Prostatic Neoplasms enzymology
- Abstract
Cyclooxygenase-2 (COX-2) is the inducible isoform of the rate-limiting enzymes that convert arachidonic acid to proinflammatory prostaglandins as well as a primary target for nonsteroidal anti-inflammatory drugs. Accumulating evidence suggests that up-regulation of COX-2 is associated with carcinogenesis in multiple organ systems including the large bowel, lung, breast, and prostate. In this report, we examine the expression of COX-2 protein and mRNA in prostate tissue containing various lesions and in prostate cancer cell lines. In the cell lines, LNCaP, DU145, PC-3, and TSU, COX-2 protein expression was undetectable under basal conditions but could be induced transiently by phorbol ester treatment in PC-3 and TSU cells, but not in DU145 and LNCaP cells. Immunohistochemical analysis of 144 human prostate cancer cases suggested that, in contrast to several previous reports, there was no consistent overexpression of COX-2 in established prostate cancer or high-grade prostatic intraepithelial neoplasia, as compared with adjacent normal prostate tissue. Positive staining was seen only in scattered cells (<1%) in both tumor and normal tissue regions but was much more consistently observed in areas of proliferative inflammatory atrophy, lesions that have been implicated in prostatic carcinogenesis. Staining was also seen at times in macrophages. Western blotting and quantitative RT-PCR analyses confirmed these patterns of expression. These results suggest that if nonsteroidal anti-inflammatory drugs are indeed chemopreventive and/or chemotherapeutic for prostate cancer, their effects are likely to be mediated by modulating COX-2 activity in non-PCa cells (either inflammatory cells or atrophic epithelial cells) or by affecting a COX-2-independent pathway.
- Published
- 2001
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