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Research Interests: Molecular Biology, Biology, Cell Biology, Transcription Factors, Medicine, and 15 moreGene expression, Western blotting, Biological Sciences, Humans, Phosphorylation, Transcription Factor, Fluorescent Antibody Technique, Base Sequence, Protein Binding, DNA binding proteins, Diploidy, Serum response factor, Molecular Sequence Data, fibroblasts, and Medical and Health Sciences
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10.1101/SQB.1988.053.01.086 Access the most recent version at doi: 1988 53: 761-767 Cold Spring Harb Symp Quant Biol ... MZ Gilman, LA Berkowitz, JR Feramisco, et al. ... References http://symposium.cshlp.org/content/53/761.refs.html This... more
10.1101/SQB.1988.053.01.086 Access the most recent version at doi: 1988 53: 761-767 Cold Spring Harb Symp Quant Biol ... MZ Gilman, LA Berkowitz, JR Feramisco, et al. ... References http://symposium.cshlp.org/content/53/761.refs.html This article cites 26 articles, 13 of ...
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Research Interests: Molecular Biology, Biology, Transcription Factors, Medicine, Biological Sciences, and 13 moreMolecular and cellular biology, Mice, Mouse, cyclic AMP, Animals, Gene, c-Fos, Enhancer, DNA binding proteins, Oligonucleotides, Gene Expression Regulation, DNA mutational analysis, and Medical and Health Sciences
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International audienc
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Abstract In the development of cancer, cells acquire the ability to autonomously control proliferation and survival. This ability comes as a result of mutations that change gene expression patterns and, in turn, alter cellular behavior.... more
Abstract In the development of cancer, cells acquire the ability to autonomously control proliferation and survival. This ability comes as a result of mutations that change gene expression patterns and, in turn, alter cellular behavior. DNA damage occurs through a variety of exogenous and endogenous sources [1] ; however, mutations only arise if there is a failure to correctly repair the damage. Thus, the ability of proteins in different repair pathways to find and repair lesions is critical in the maintenance of genome stability and prevention of cancer. Work in the chromatin field has led to a fuller understanding of how DNA damage is detected and repaired and the structure of chromatin has become a focal point. Chromatin is targeted for modifications at the lesion site to enable accurate DNA repair and must be reassembled afterward. In this chapter, we summarize the factors regulating chromatin changes that are critical in mediating the repair of DNA damage.
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ING2 (Inhibitor of Growth 2) is a tumor-suppressor gene involved in chromatin acetylation whose loss has been observed in nearly 60% of NSCLC. The loss of ING2 expression has been associated with the progression of tumor cells from G1 to... more
ING2 (Inhibitor of Growth 2) is a tumor-suppressor gene involved in chromatin acetylation whose loss has been observed in nearly 60% of NSCLC. The loss of ING2 expression has been associated with the progression of tumor cells from G1 to S phase, replication stress and genomic instability. The intra-S and the G2-M phase checkpoints are mainly regulated by the cell cycle tyrosine kinase WEE1. Therefore, we hypothesized that the loss of ING2 expression could sensitize NSCLC to the WEE1 inhibitor MK-1175, according to a synthetic lethality model. In silico analysis of the cancer gene dependency map (shRNAi Achilles library v.2016) was used to explore gene interactions with ING2. Antiproliferative effects of drugs were tested in vitro with AlamarBlue and MTT assays in a panel of NSCLC cells lines with varied mutational status. Multiple functional approaches were taken to decrease ING2 expression in RAS-mutated NSCLC cell lines (si-RNA, LNA-gapmer, and CrispR-Cas9). Pharmacologic inhibit...
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The inhibitor of growth (ING) family of zinc-finger plant homeodomain (PHD)-containing chromatin remodeling protein controls gene expression and has been implicated in the regulation of cell proliferation and death. However, the role of... more
The inhibitor of growth (ING) family of zinc-finger plant homeodomain (PHD)-containing chromatin remodeling protein controls gene expression and has been implicated in the regulation of cell proliferation and death. However, the role of ING proteins in cell differentiation remains largely unexplored. Here, we identify an essential function for ING2 in muscle differentiation. We find that knockdown of ING2 by RNA interference (RNAi) blocks the differentiation of C2C12 cells into myotubes, suggesting that ING2 regulates the myogenic differentiation program. We also characterize a mechanism by which ING2 drives muscle differentiation. In structure-function analyses, we find that the leucine zipper motif of ING2 contributes to ING2-dependent muscle differentiation. By contrast, the PHD domain, which recognizes the histone H3K4me3 epigenetic mark, inhibits the ability of ING2 to induce muscle differentiation. We also find that the Sin3A-HDAC1 chromatin remodeling complex, which interacts...
Telomeres are protective structures, composed of nucleic acids and a complex protein mixture, located at the end of the chromosomes. They play an important role in preventing genomic instability and ensuring cell health. Defects in... more
Telomeres are protective structures, composed of nucleic acids and a complex protein mixture, located at the end of the chromosomes. They play an important role in preventing genomic instability and ensuring cell health. Defects in telomere integrity result in cell dysfunction and the development of diseases, including neurodegenerative disorders, cancer and premature aging syndromes, among others. Loss of telomere integrity during normal cell aging also initiates DNA damage signals that culminate in the senescence phenotype. Fluorescence microscopy has allowed researchers to study the dynamics, shape, localization, and co-distribution of telomeres with proteins of interest. The microscopy tools to investigate these structures have evolved, making it possible to understand in greater detail the molecular mechanisms affecting telomeres that contribute to cell aging and the development of age-related diseases. Using human fibroblasts as an example, we will highlight several characteristics of telomeres that can be investigated using three different microscopy systems, including wide-field microscopy, and the two super-resolution techniques called 3D Structured Illumination Microscopy (3D-SIM) and direct Stochastic Optical Reconstruction Microscopy (dSTORM). In this review, we will also discuss their limitations and highlight their importance in answering telomere-related scientific questions.
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Mammalian development involves an exquisite choreography of cell division, differentiation, locomotion, programmed cell death, and senescence that directs the transformation of a single cell zygote to a mature organism containing on the... more
Mammalian development involves an exquisite choreography of cell division, differentiation, locomotion, programmed cell death, and senescence that directs the transformation of a single cell zygote to a mature organism containing on the order of 40 trillion cells in humans. How a single totipotent zygote undergoes the rapid stages of embryonic development to form over 200 different cell types is complex in the extreme and remains the focus of active research. Processes such as programmed cell death or apoptosis has long been known to occur during development to help sculpt organs and tissue systems. Other processes such as cellular senescence, long thought to only occur in pathologic states such as aging and tumorigenesis have been recently reported to play a vital role in development. In this review, we focus on apoptosis and senescence; the former as an integral mechanism that plays a critical role not only in mature organisms, but that is also essential in shaping mammalian devel...
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Telomere length and dynamics are central to understanding cell aging, genomic instability and cancer. Currently, there are limited guidelines for analyzing telomeric features in 3D using different cellular models. Image processing for... more
Telomere length and dynamics are central to understanding cell aging, genomic instability and cancer. Currently, there are limited guidelines for analyzing telomeric features in 3D using different cellular models. Image processing for telomere analysis is of increasing interest in many fields, however a lack of standardization can make comparisons and reproducibility an issue. Here we provide a user's guide for quantitative immunofluorescence microscopy of telomeres in interphase cells that covers image acquisition, processing and analysis. Strategies for determining telomere size and number are identified using normal human diploid Hs68 fibroblasts. We demonstrate how to accurately determine telomere number, length, volume, and degree of clustering using quantitative immunofluorescence. Using this workflow, we make the unexpected observation that hTERT-immortalized Hs68 cells with longer telomeres have fewer resolvable telomeres in interphase. Rigorous quantification indicates ...
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The proteins belonging to the inhibitor of growth (ING) family of proteins serve as epigenetic readers of the H3K4Me3 histone mark of active gene transcription and target histone acetyltransferase (HAT) or histone deacetylase (HDAC)... more
The proteins belonging to the inhibitor of growth (ING) family of proteins serve as epigenetic readers of the H3K4Me3 histone mark of active gene transcription and target histone acetyltransferase (HAT) or histone deacetylase (HDAC) protein complexes, in order to alter local chromatin structure. These multidomain adaptor proteins interact with numerous other proteins to facilitate their localization and the regulation of numerous biochemical pathways that impinge upon biological functions. Knockout of some of the ING genes in murine models by various groups has verified their status as tumor suppressors, with ING1 knockout resulting in the formation of large clear-cell B-lymphomas and ING2 knockout increasing the frequency of ameloblastomas, among other phenotypic effects. ING4 knockout strongly affects innate immunity and angiogenesis, and INGs1, ING2, and ING4 have been reported to affect apoptosis in different cellular models. Although ING3 and ING5 knockouts have yet to be publi...
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Replicative capacity of normal human cells decreases as telomeric sequence is lost at each division. It is believed that when a subset of chromosomes reach a critically short length, an ATM-initiated and p53-mediated transcriptional... more
Replicative capacity of normal human cells decreases as telomeric sequence is lost at each division. It is believed that when a subset of chromosomes reach a critically short length, an ATM-initiated and p53-mediated transcriptional response inhibits cell growth, promoting cell senescence. In addition to loss of telomeric sequence, senescence can be induced by other stresses including ionizing radiation, oxidative damage, chemical crosslinkers like the chemotherapeutic agent cisplatin, as well as overactivation of oncogenes and tumor suppressors. Our group found that the expression of an isoform of the INhibitor of Growth 1 gene called ING1a increases approximately 10-fold as fibroblasts approach senescence and that forced expression rapidly induces a senescent phenotype in primary diploid fibroblasts, epithelial and endothelial cells that resembles replicative senescence by most physical and biochemical measures. ING1a induces these changes through strongly inhibiting endocytosis t...
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Purpose: The current study was designed to investigate the combined influence of ataxia telangiectasia mutated (ATM) and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients... more
Purpose: The current study was designed to investigate the combined influence of ataxia telangiectasia mutated (ATM) and Ki67 on clinical outcome in early stage hormone receptor positive breast cancer (ES-HPBC), particularly in patients with smaller tumors (< 4 cm) and fewer than four positive lymph nodes. Methods: Formalin-fixed paraffin-embedded specimens of resected primary breast tumors from 532 patients diagnosed with early stage breast cancer were used to construct a tissue microarray. Samples from 297 patients were suitable for final statistical analysis. We detected ATM and Ki67 proteins using immunohistochemistry and quantified their expression with digital image analysis. Data on expression levels were subsequently correlated with clinical outcome. Results: Remarkably, ATM expression was useful to stratify the low Ki67 group into subgroups with better or poorer prognosis. Specifically, in the low Ki67 subgroup defined as having smaller tumors and no positive nodes, pati...
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The ING family of type II tumour suppressors serve as both epigenetic 'readers' and target histone acetyl transferase (HAT) and histone deacetylase (HDAC) 'writers' of the epigenetic histone code. The ING1 protein has also... more
The ING family of type II tumour suppressors serve as both epigenetic 'readers' and target histone acetyl transferase (HAT) and histone deacetylase (HDAC) 'writers' of the epigenetic histone code. The ING1 protein has also been implicated in regulating microRNA (miRNA) levels. In this study, we identify a link between ING1b and the miRNA epigenetic network. Primary fibroblasts infected with adenoviruses expressing GFP control or GFP plus ING1b were examined for alterations in miRNA profiles using a miRNA PCR array. Additional experiments confirmed specificity and consequences of altered miRNA expression. MicroRNAs miR-203, miR-375, miR-449b and miR-200c were increased by ING1b overexpression. Ectopic expression of miR-203 inhibited U2OS and MDA-MB-231 cancer cell growth, and induced G1 cell cycle arrest in U2OS cells as estimated by flow cytometry. Transfection with miR-203 inhibitor reversed the proliferation inhibition induced by ING1b in U2OS cells. CHIP assays sh...
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To define the molecular bases of growth factor-induced signal transduction pathways, antibodies known to block the activity of either protein kinase C (PKC) or the fos protein were introduced into PC12 cells by microinjection. The... more
To define the molecular bases of growth factor-induced signal transduction pathways, antibodies known to block the activity of either protein kinase C (PKC) or the fos protein were introduced into PC12 cells by microinjection. The antibody against PKC significantly inhibited neurite outgrowth when scored 24 h after microinjection and exposure to nerve growth factor (NGF). Microinjection of antibodies to fos significantly increased the percentage of neurite-bearing cells after exposure to either NGF or basic fibroblast growth factor (bFGF) but inhibited the stimulation of DNA synthesis by serum, suggesting that in PC12 cells, fos is involved in cellular proliferation. Thus, activation of PKC is involved in the induction of neurite outgrowth by NGF, but expression of the fos protein, which is induced by both NGF and bFGF, is not necessary and inhibits neurite outgrowth.
Research Interests: Neurogenesis, Biology, Cell Biology, Medicine, Cell Division, and 14 moreSignal Transduction, Biological Sciences, Antibodies, Animals, Monoclonal Antibodies, Fibroblast Growth Factor, Microinjection, Rats, Neurite, Nerve Growth Factor, Protein Kinase C, Medical and Health Sciences, Basic Fibroblast Growth Factor, and Fibroblast growth factors
Human diploid fibroblasts (HDFs) undergo a limited number of population doublings in culture before reaching the end of their proliferative life span, an event termed in vitro cellular senescence. Considerable evidence suggests that... more
Human diploid fibroblasts (HDFs) undergo a limited number of population doublings in culture before reaching the end of their proliferative life span, an event termed in vitro cellular senescence. Considerable evidence suggests that altered expression of key genes involved in the mitogenic response may be responsible for the inability of senescent cells to proliferate. Here we examined the expression and activity of the early growth response-1 (egr-1) gene, an &quot;immediate-early&quot; gene that is believed to link extracellular mitogenic signals to cell-cycle progression. We found that egr-1 was strongly downregulated in senescent HDFs at the level of mRNA, protein, and DNA binding activity. Decreased DNA binding activity of Egr-1 in vitro corresponded to decreased transcriptional activation in vivo. To further understand the mechanism of egr-1 downregulation, we examined the potential role of the serum response elements (SREs) present in the egr-1 promoter. Electrophoretic mobility shift studies using young and old cell nuclear extracts showed a marked decrease in serum response factor (SRF) binding activity to the SRE in old compared to young cells. Loss of SRF binding activity has been correlated with the loss of expression of another growth-related immediate-early gene (c-fos). These results suggest a common mechanism for the downregulation of c-fos, egr-1, and other SRE-dependent, mitogen-responsive genes during cellular senescence.
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10.1101/SQB.1988.053.01.086 Access the most recent version at doi: 1988 53: 761-767 Cold Spring Harb Symp Quant Biol ... MZ Gilman, LA Berkowitz, JR Feramisco, et al. ... References http://symposium.cshlp.org/content/53/761.refs.html This... more
10.1101/SQB.1988.053.01.086 Access the most recent version at doi: 1988 53: 761-767 Cold Spring Harb Symp Quant Biol ... MZ Gilman, LA Berkowitz, JR Feramisco, et al. ... References http://symposium.cshlp.org/content/53/761.refs.html This article cites 26 articles, 13 of ...
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This article cites 77 articles, 31 of which can be accessed free at:
The human genome's spectrum of gene expression patterns is vast and, while constantly adapting to surrounding cues, versatile and variable. It generates hundreds of different cell types forming multiple tissues and organ systems [1],... more
The human genome's spectrum of gene expression patterns is vast and, while constantly adapting to surrounding cues, versatile and variable. It generates hundreds of different cell types forming multiple tissues and organ systems [1], amongst which well over a hundred cancer types have been identified to date [1]. While originating from the same ancestor, thereby harboring nearly identical genetic information, every eukaryotic cell type presents with its own distinguishable biological behavior and phenotype, underscoring the degree of cell plasticity inherent during development. Instead of being established by DNA sequence alterations, the rich diversity of cell identities is now thought to be defined and largely driven by epigenetic variation—a regulatory engine fueled by the homeostatic balance of chromatin regulators and designed to maintain physiological organismal homeostasis to ensure functional gene expression in both stressful and quiescent situations. Disruption of chrom...
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Lung cancer is the leading cause of cancer death in the U.S. and remains the least-funded cancer in North America. Many studies addressed disparities in lung cancer incidence rate among the races; however, few studies described the effect... more
Lung cancer is the leading cause of cancer death in the U.S. and remains the least-funded cancer in North America. Many studies addressed disparities in lung cancer incidence rate among the races; however, few studies described the effect of both race and gender in the risk of manifesting this disease. These studies lack consensus for both the etiology and the magnitude of gender-based disparities and their impact on disease development on specific racial groups. These unknown race-associated characteristics between men and women might adversely affect the improvement of current therapies and patient outcomes. Characterizing gender as a possible risk modifier in lung cancer development among certain ethnic groups may aid in the development of targeted agents that improve patient outcomes. This study aimed to investigate the global pattern of gender-based disparities in incidence of lung cancer and describe the etiologic factors associated with different racial groups in non-small ce...
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To assess oncogenic potential, classical transformation assays are based on cell line models. However, cell line based models do not reflect the complexity of human tissues. We thus developed an inducible expression system for gene... more
To assess oncogenic potential, classical transformation assays are based on cell line models. However, cell line based models do not reflect the complexity of human tissues. We thus developed an inducible expression system for gene expression in ex vivo human tissues, which maintain native tissue architecture, such as epithelia and stroma. To validate the system, we transduced and expressed known tumor suppressors (p53, p33ING1b), oncoproteins (RasV12, p47ING3), or controls (empty vector, YFP) in ex vivo prostate tissues, then assessed proliferation by immunohistochemistry of markers (H3S10phos). Herein, we describe how to generate lentiviral vectors and particules, successfully transduce human prostate tissues, induce exogenous gene expression, and assess cellular proliferation.
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Transcription of the protooncogene c-fos is increased greater than 10-fold within minutes of treatment of fibroblasts with serum or purified growth factors. Recent experiments with mouse 3T3 cell lines containing inducible fos antisense... more
Transcription of the protooncogene c-fos is increased greater than 10-fold within minutes of treatment of fibroblasts with serum or purified growth factors. Recent experiments with mouse 3T3 cell lines containing inducible fos antisense RNA constructs have shown that induced fos antisense RNA transcripts cause either a marked inhibition of growth in continuously proliferating cells or, conversely, a minimal effect except during the transition from a quiescent (G0) state into the cell cycle. Since intracellular production of large amounts of antisense RNA does not completely block gene expression, we microinjected affinity-purified antibodies raised against fos to determine whether and when during the cell cycle c-fos expression was required for cell proliferation. Using this independent method, we found that microinjected fos antibodies efficiently blocked serum-stimulated DNA synthesis when injected up to 6 to 8 h after serum stimulation of quiescent REF-52 fibroblasts. Furthermore...
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Research Interests: Biology, Cell Cycle, Cell Biology, DNA damage, Apoptosis, and 15 moreBiological Sciences, Cell line, Environmental Sciences, Humans, Alternative splicing, Animal Model, Green Fluorescent Protein, Amino Acid Profile, Alternative Splicing, Amino Acid Sequence, Human Fibroblasts, Cell Cycle Proteins, Fusion Protein, DNA binding proteins, and fibroblasts
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The p33ING1 protein is a regulator of cell cycle, senescence, and apoptosis. Three alternatively spliced transcripts of p33ING1 encode p47ING1a, p33ING1b, and p24ING1c. We cloned an additional ING family member, p33ING2 / ING1L . Unlike... more
The p33ING1 protein is a regulator of cell cycle, senescence, and apoptosis. Three alternatively spliced transcripts of p33ING1 encode p47ING1a, p33ING1b, and p24ING1c. We cloned an additional ING family member, p33ING2 / ING1L . Unlike p33ING1b, p33ING2 is induced by the DNA-damaging agents etoposide and neocarzinostatin. p33ING1b and p33ING2 negatively regulate cell growth and survival in a p53-dependent manner through induction of G 1 -phase cell-cycle arrest and apoptosis. p33ING2 strongly enhances the transcriptional-transactivation activity of p53. Furthermore, p33ING2 expression increases the acetylation of p53 at Lys-382. Taken together, p33ING2 is a DNA damage-inducible gene that negatively regulates cell proliferation through activation of p53 by enhancing its acetylation.
Research Interests: Biology, Cell Cycle, Cell Biology, Gamma Rays, DNA damage, and 15 moreApoptosis, Medicine, Cell Division, Humans, Cisplatin, Molecular cloning, Doxorubicin, Acetylation, Bleomycin, Cell Proliferation, Amino Acid Sequence, Gene Expression Regulation, Cell Growth, Molecular Sequence Data, and Etoposide
ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21... more
ING proteins affect apoptosis, growth, and DNA repair by transducing stress signals such as DNA damage, binding histones, and subsequently regulating chromatin structure and p53 activity. p53 target genes, including the p21 cyclin-dependent kinase inhibitor and Bax, an inducer of apoptosis, are regulated by ING proteins. To identify additional targets downstream of p33 ING1 and p32 ING2 , cDNA microarrays were performed on phenotypically normal human primary fibroblasts. The 0.36% of genes affected by ING proteins in primary fibroblasts were distinct from targets seen in established cells and included the HSP70 heat shock gene, whose promoter was specifically induced >10-fold. ING1-induced expression of HSP70 shifted cells from survival to a death pathway in response to tumor necrosis factor alpha (TNF-α), and p33 ING1b protein showed synergy with TNF-α in inducing apoptosis, which correlated with reduced NF-κB-dependent transcription. These findings are consistent with previous ...
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Research Interests: Biology, Biological Chemistry, Apoptosis, Medicine, Biological Sciences, and 14 moreCell line, Humans, Biological, Proteins, CHEMICAL SCIENCES, Histones, Histone acetyltransferases, Acetylation, Histone, Cell Cycle Proteins, DNA binding proteins, Histone Acetylation, Down-Regulation, and Medical and Health Sciences
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The ING1 epigenetic regulator and tumor suppressor plays a central role in apoptosis. The Ing1 gene is functionally inactivated in many cancer types but is rarely mutated. Although most studies have implicated the major ING1 isoform,... more
The ING1 epigenetic regulator and tumor suppressor plays a central role in apoptosis. The Ing1 gene is functionally inactivated in many cancer types but is rarely mutated. Although most studies have implicated the major ING1 isoform, p33ING1b, in nuclear apoptotic signalling, we recently discovered a novel and potent apoptosis-inducing effect of p33ING1b translocation to the mitochondria in response to DNA damage. In the present study, we examined the impact of cytoplasmic/mitochondrial localization of p33ING1b in oral squamous cell carcinoma (OSCC) patient samples and explored the therapeutic potential of adenovirally-overexpressed p33ING1b in OSCC cell lines in combination with ionizing radiation (IR) treatment. In contrast with previous reports, we found that p33ING1b protein and mRNA levels are higher in OSCC compared to normal epithelial cells. In OSCC patient samples, higher levels of intra-tumoral cytoplasmic p33ING1b correlated with increased apoptotic markers and significan...
Research Interests: Cancer, Biology, Immunohistochemistry, Cancer Research, Apoptosis, and 13 moreMedicine, Western blotting, Humans, Female, Male, Head and neck squamous cell carcinoma, Middle Aged, Oral Squamous Cell Carcinoma (OSCC), Cell nucleus, Mouth Neoplasms, Cytoplasm, Proportional Hazards Models, and Protein Transport
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Telomerase, the enzyme that maintains the ends of linear eukaryotic chromosomes, is active in human germ cells and in a majority of tumor tissues and immortalized cell lines. In contrast, most mature somatic cells and tissues contain low... more
Telomerase, the enzyme that maintains the ends of linear eukaryotic chromosomes, is active in human germ cells and in a majority of tumor tissues and immortalized cell lines. In contrast, most mature somatic cells and tissues contain low or undetectable telomerase activity, implying a stringent negative regulatory control mechanism. We report here that telomerase activity is dramatically inhibited during the terminal differentiation of HL-60 human promyelocytic leukemia cells to monocytic and granulocytic lineages. A loss of telomerase activity was seen in response to three different inducers of differentiation, was independent of differentiation-induced apoptosis, and occurred in the presence of unaltered expression of the RNA component of telomerase. Reduction in telomerase activity was also observed during the differentiation of murine F9 teratocarcinoma and C2C12 myoblast cells. In contrast, induced differentiation of murine p19 embryonal carcinoma and Neuro 2a neuroblastoma cel...
Research Interests: Cancer, Biology, Medicine, Telomerase, DNA, and 10 moreCell line, Cell Differentiation, Humans, Mice, Animals, Enzyme, Tretinoin, Germ Cell, Somatic Cells, and Embryonal carcinoma
Telomerase, the enzyme that maintains the ends of linear eukaryotic chromosomes, is active in human germ cells and in a majority of tumor tissues and immortalized cell lines. In contrast, most mature somatic cells and tissues contain low... more
Telomerase, the enzyme that maintains the ends of linear eukaryotic chromosomes, is active in human germ cells and in a majority of tumor tissues and immortalized cell lines. In contrast, most mature somatic cells and tissues contain low or undetectable telomerase activity, implying a stringent negative regulatory control mechanism. We report here that telomerase activity is dramatically inhibited during the terminal differentiation of HL-60 human promyelocytic leukemia cells to monocytic and granulocytic lineages. A loss of telomerase activity was seen in response to three different inducers of differentiation, was independent of differentiation-induced apoptosis, and occurred in the presence of unaltered expression of the RNA component of telomerase. Reduction in telomerase activity was also observed during the differentiation of murine F9 teratocarcinoma and C2C12 myoblast cells. In contrast, induced differentiation of murine p19 embryonal carcinoma and Neuro 2a neuroblastoma cel...
Research Interests: Cancer, Biology, Medicine, Telomerase, DNA, and 10 moreCell line, Cell Differentiation, Humans, Mice, Animals, Enzyme, Tretinoin, Germ Cell, Somatic Cells, and Embryonal carcinoma
Recently, several novel human ING1 isoforms have been cloned. However,the biochemical functions and the involvement of these proteins in apoptosis remain uncharacterized. We have examined the apoptotic effects and biochemical functions of... more
Recently, several novel human ING1 isoforms have been cloned. However,the biochemical functions and the involvement of these proteins in apoptosis remain uncharacterized. We have examined the apoptotic effects and biochemical functions of the two major human ING1 isoforms p47(ING1a) and p33(ING1b) in young and senescent human diploid fibroblasts induced to enter into apoptosis by diverse treatments. We have found that ING1 displayed isoform-, stimulus- and cell age-dependent apoptotic properties. We present evidence indicating that ING1 proteins bind to chromatin and are regulated in a manner related to their apoptotic properties. In agreement with previous reports, we have found that only young but not senescent fibroblasts were able to enter into apoptosis induced by growth factor deprivation. This effect was accompanied by up-regulation of endogenous p33(ING1b). Ectopic up-regulation of p33(ING1b), but not p47(ING1a), also induced apoptosis and sensitized young but not senescent ...
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PURPOSE Clinical and experimental evidence suggest that the p33ING1b candidate tumor suppressor functionally cooperates with p53 in controlling biochemical and biological functions. Because p53 is frequently mutated in brain tumors and... more
PURPOSE Clinical and experimental evidence suggest that the p33ING1b candidate tumor suppressor functionally cooperates with p53 in controlling biochemical and biological functions. Because p53 is frequently mutated in brain tumors and the ING1 locus maps to a site of which the loss is associated with gliomas, we analyzed the mutation and expression profiles of ING1B in human brain tumors. Here we present the first report of ING1 expression and mutation analyses in human brain tumor samples and malignant glioma cell lines. EXPERIMENTAL DESIGN Expression and mutation analyses of ING1B together with subcellular localization studies of ING1 proteins were performed on 29 brain tumor specimens and 6 human glioma cell lines. RESULTS A single point mutation (3.5%) was detected in the 29 brain tumor specimens analyzed. This missense mutation occurred in a sequence reported previously to confer nuclear translocation properties to p33ING1b. Interestingly, overexpression and subcellular misloc...