11 results on '"Rizos, Helen"'
Search Results
2. p16(INK) (4a) deficiency promotes DNA hyper-replication and genetic instability in melanocytes.
- Author
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Fung C, Pupo GM, Scolyer RA, Kefford RF, and Rizos H
- Subjects
- Cell Cycle Checkpoints genetics, Cell Proliferation, Cyclin-Dependent Kinases metabolism, DNA Damage genetics, HEK293 Cells, Histones metabolism, Humans, Melanocytes enzymology, Nevus metabolism, Nevus pathology, Retinoblastoma Protein metabolism, Tumor Suppressor Protein p53 metabolism, Cyclin-Dependent Kinase Inhibitor p16 deficiency, Cyclin-Dependent Kinase Inhibitor p16 metabolism, DNA Replication, Genomic Instability, Melanocytes metabolism, Melanocytes pathology
- Abstract
Activated oncogenes restrict cell proliferation and transformation by triggering a DNA damage-dependent senescence checkpoint in response to DNA hyper-replication. Here, we show that loss of the p16(INK) (4a) cyclin-dependent kinase inhibitor and melanoma tumour suppressor facilitates a DNA damage response after a hyper-replicative phase in human melanocytes. Unlike cells expressing activated oncogenes, however, melanocytes depleted for p16(INK) (4a) display enhanced proliferation and an extended replicative lifespan in the presence of replication-associated DNA damage. Analysis of human benign naevi confirmed that DNA damage and loss of p16(INK) (4a) expression co-segregate closely. Thus, we propose that loss of p16(INK) (4a) facilitates tumourigenesis by promoting the proliferation of genetically unstable cells., (© 2012 John Wiley & Sons A/S.)
- Published
- 2013
- Full Text
- View/download PDF
3. Monitoring oncogenic B-RAF-induced senescence in melanocytes.
- Author
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Tran SL and Rizos H
- Subjects
- Bromodeoxyuridine metabolism, Cell Culture Techniques, Cell Line, Tumor, Humans, Lentivirus genetics, Melanocytes metabolism, Microscopy, Fluorescence, Mutation, Skin cytology, Staining and Labeling, Transduction, Genetic, Transgenes genetics, beta-Galactosidase metabolism, Cellular Senescence genetics, Genetic Engineering methods, Melanocytes cytology, Oncogenes genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
The B-RAF kinase is a downstream effector of the RAS family of proto-oncogenes and is constitutively activated in the majority of human melanomas. The common oncogenic B-RAF(V600E) mutant cooperates with additional genetic lesions to transform immortal murine and human cells. In primary cells, however, B-RAF(V600E) triggers a rapid cell cycle arrest that is phenotypically indistinguishable from cellular senescence. Here we describe the analyses of B-RAF-induced senescence in primary human melanocytes using recombinant lentiviruses.
- Published
- 2013
- Full Text
- View/download PDF
4. Differential PAX3 functions in normal skin melanocytes and melanoma cells.
- Author
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Medic S, Rizos H, and Ziman M
- Subjects
- Cell Line, Cell Line, Tumor, Cell Movement, Cell Proliferation, Humans, Melanocytes cytology, Melanocytes pathology, Melanoma pathology, PAX3 Transcription Factor, Paired Box Transcription Factors genetics, Skin cytology, Skin pathology, Skin Neoplasms pathology, Melanocytes metabolism, Melanoma metabolism, Paired Box Transcription Factors physiology, Skin metabolism, Skin Neoplasms metabolism
- Abstract
The PAX3 transcription factor is the key regulator of melanocyte development during embryogenesis and is also frequently found in melanoma cells. While PAX3 is known to regulate melanocyte differentiation, survival, proliferation and migration during development, it is not clear if its function is maintained in adult melanocytes and melanoma cells. To clarify this we have assessed which genes are targeted by PAX3 in these cells. We show here that similar to its roles in development, PAX3 regulates complex differentiation networks in both melanoma cells and melanocytes, in order to maintain cells as "stem" cell-like (via NES and SOX9). We show also that mediators of migration (MCAM and CSPG4) are common to both cell types but more so in melanoma cells. By contrast, PAX3-mediated regulation of melanoma cell proliferation (through TPD52) and survival (via BCL2L1 and PTEN) differs from that in melanocytes. These results suggest that by controlling cell proliferation, survival and migration as well as maintaining a less differentiated "stem" cell like phenotype, PAX3 may contribute to melanoma development and progression., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
- Full Text
- View/download PDF
5. Oncogene-induced senescence pathways in melanocytes.
- Author
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Haferkamp S and Rizos H
- Subjects
- Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Humans, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Cellular Senescence physiology, Melanocytes physiology, Oncogenes, Signal Transduction physiology
- Published
- 2010
- Full Text
- View/download PDF
6. Oncogenic B-RAF(V600E) promotes anchorage-independent survival of human melanocytes.
- Author
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Becker TM, Philipsz S, Scurr LL, Fung C, Haferkamp S, Kefford RF, and Rizos H
- Subjects
- Anoikis physiology, Cell Adhesion physiology, Cell Survival physiology, Humans, Melanocytes metabolism, Melanoma genetics, Melanoma physiopathology, Proto-Oncogene Proteins B-raf metabolism, Skin Neoplasms genetics, Skin Neoplasms physiopathology, Melanocytes physiology, Melanoma pathology, Point Mutation, Proto-Oncogene Proteins B-raf genetics, Skin Neoplasms pathology
- Published
- 2010
- Full Text
- View/download PDF
7. Oncogene-induced senescence does not require the p16(INK4a) or p14ARF melanoma tumor suppressors.
- Author
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Haferkamp S, Scurr LL, Becker TM, Frausto M, Kefford RF, and Rizos H
- Subjects
- Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases physiology, Humans, Melanoma pathology, Proto-Oncogene Proteins c-akt physiology, Cellular Senescence, Cyclin-Dependent Kinase Inhibitor p16 physiology, Genes, ras, Melanocytes cytology, Melanoma prevention & control, Tumor Suppressor Protein p14ARF physiology, Tumor Suppressor Proteins physiology
- Abstract
Oncogene-induced senescence is considered to act as a potent barrier to cell transformation, and has been seen in vivo during the early stages of tumor development. Human nevus cells frequently express oncogenic N-RAS or B-RAF, and are thought to be permanently growth arrested. Many studies have suggested that the p16(INK4a) and, to a lesser extent, the p14ARF tumor suppressor proteins act as critical triggers of oncogene-induced senescence in nevi, and thus these proteins represent major inhibitors of progression to melanoma. There have also been reports, however, showing that p16(INK4a) and/or p14ARF is not sufficient to execute the oncogene-induced senescence program. In this study, we examined the impact of melanoma-associated N-RAS(Q61K) on melanocyte senescence and utilized RNA-interference vectors to directly assess the individual contribution of human p14ARF and p16(INK4a) genes to the N-RAS-induced senescence program. We formally show that cultured human melanocytes can initiate an effective oncogene-mediated senescence program in the absence of INK4a/ARF-encoded proteins. Our data are consistent with observations showing that senescent nevus cells do not always express p16(INK4a), and highlight the need to thoroughly explore INK4a/ARF-independent molecular pathways of senescence in human melanocytes.
- Published
- 2009
- Full Text
- View/download PDF
8. The relative contributions of the p53 and pRb pathways in oncogene-induced melanocyte senescence.
- Author
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Haferkamp S, Tran SL, Becker TM, Scurr LL, Kefford RF, and Rizos H
- Subjects
- Cell Line, Tumor, Cell Proliferation, Cellular Senescence genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Cyclin-Dependent Kinase Inhibitor p16 metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics, Cyclin-Dependent Kinase Inhibitor p21 metabolism, DNA Damage, Gene Silencing, Humans, Melanocytes cytology, Retinoblastoma genetics, Tumor Suppressor Protein p53 genetics, Melanocytes metabolism, Retinoblastoma metabolism, Tumor Suppressor Protein p53 metabolism
- Abstract
Oncogene-induced senescence acts as a barrier against tumour formation and has been implicated as the mechanism preventing the transformation of benign melanocytic lesions that frequently harbour oncogenic B-RAF or N-RAS mutations. In the present study we systematically assessed the relative importance of the tumour suppressor proteins p53, p21(Waf1), pRb and p16(INK4a) in mediating oncogene-induced senescence in human melanocytes. We now show that oncogenic N-RAS induced senescence in melanocytes is associated with DNA damage, a potent DNA damage response and the activation of both the p16(INK4a)/pRb and p53/p21(Waf1) tumour suppressor pathways. Surprisingly neither the pharmacological inhibition of the DNA damage response pathway nor silencing of p53 expression had any detectable impact on oncogene-induced senescence in human melanocytes. Our data indicate that the pRb pathway is the dominant effector of senescence in these cells, as its specific inactivation delays the onset of senescence and weakens oncogene-induced proliferative arrest. Furthermore, we show that although both p16(INK4a) and p21(Waf1) are upregulated in response to N-RAS(Q61K), the activities of these CDK inhibitors are clearly distinct and only the loss of p16(INK4a) weakens senescence. We propose that the ability of p16(INK4a) to inhibit the cyclin D-dependent kinases and DNA replication, functions not shared by p21(Waf1), contribute to its role in senescence. Thus, in melanocytes with oncogenic signalling only p16(INK4a) can fully engage the pRb pathway to alter chromatin structure and silence the genes that are required for proliferation.
- Published
- 2009
- Full Text
- View/download PDF
9. p16 INK4a deficiency promotes DNA hyper-replication and genetic instability in melanocytes.
- Author
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Fung, Carina, Pupo, Gulietta M., Scolyer, Richard A., Kefford, Richard F., and Rizos, Helen
- Subjects
P16 gene ,DNA replication ,MELANOCYTES ,CYCLIN-dependent kinase inhibitors ,GENETICS ,ONCOGENES ,CELL proliferation - Abstract
Activated oncogenes restrict cell proliferation and transformation by triggering a DNA damage-dependent senescence checkpoint in response to DNA hyper-replication. Here, we show that loss of the p16
INK 4a cyclin-dependent kinase inhibitor and melanoma tumour suppressor facilitates a DNA damage response after a hyper-replicative phase in human melanocytes. Unlike cells expressing activated oncogenes, however, melanocytes depleted for p16INK 4a display enhanced proliferation and an extended replicative lifespan in the presence of replication-associated DNA damage. Analysis of human benign naevi confirmed that DNA damage and loss of p16INK 4a expression co-segregate closely. Thus, we propose that loss of p16INK 4a facilitates tumourigenesis by promoting the proliferation of genetically unstable cells. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
10. Absence of Distinguishing Senescence Traits in Human Melanocytic Nevi.
- Author
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Tran, Sieu L, Haferkamp, Sebastian, Scurr, Lyndee L, Gowrishankar, Kavitha, Becker, Therese M, Desilva, Chitra, Thompson, John F, Scolyer, Richard A, Kefford, Richard F, and Rizos, Helen
- Subjects
- *
CELLULAR aging , *TUMOR suppressor genes , *MELANOCYTES , *NEVUS , *GALACTOSIDASES , *DISEASES - Abstract
Cellular senescence permanently restricts the replicative capacity of cells in response to various stress signals, including aberrant activation of oncogenes. The presence of predictive senescence markers in human premalignant lesions suggests that senescence may function as a genuine tumor suppressor. These markers are not exclusive to the senescence program, however, and it is possible that their expression in vivo does not discriminate irreversible from reversible forms of proliferative arrest. In this study, we aimed to clarify whether human nevus cells can be distinguished from primary and transformed melanocytes by examining the expression of eight senescence markers, including those previously purported to define nevi as senescent tumors. Specifically, we analyzed effectors of senescence, including p16INK4a, p53, and DNA damage (γ-H2AX), as well as predictive markers of senescence including Ki67, PML, senescence-associated β-galactosidase, heterochromatic foci (H3K9Me, 4′-6-diamidino-2-phenylindole), and nuclear size. We found that these commonly accepted senescence markers do not in fact distinguish nevi from precursor/normal and transformed/malignant melanocytes. We conclude that on the basis of current evidence it cannot be reasonably inferred that nevi are permanently growth arrested via senescence. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
11. Oncogenic B-RAFV600E Promotes Anchorage-Independent Survival of Human Melanocytes.
- Author
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Becker, Therese M., Philipsz, Suzanah, Scurr, Lyndee L., Fung, Carina, Haferkamp, Sebastian, Kefford, Richard F., and Rizos, Helen
- Subjects
- *
LETTERS to the editor , *MELANOCYTES - Abstract
A letter to the editor is presented regarding the effect of oncogenic B-RAFV600E on the survival of human melanocytes.
- Published
- 2010
- Full Text
- View/download PDF
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