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RB Pathway (rb + pathway)
Selected AbstractsIntegrated genomic profiling identifies candidate genes implicated in glioma-genesis and a novel LEO1 - SLC12A1 fusion geneGENES, CHROMOSOMES AND CANCER, Issue 6 2010Linda B. C. Bralten We performed genotyping and exon-level expression profiling on 21 glioblastomas (GBMs) and 19 oligodendrogliomas (ODs) to identify genes involved in glioma initiation and/or progression. Low-copy number amplifications (2.5 < n < 7) and high-copy number amplifications (n > 7) were more frequently observed in GBMs; ODs generally have more heterozygous deletions per tumor. Four high-copy amplicons were identified in more than one sample and resulted in overexpression of the known oncogenes EGFR, MDM2, and CDK4. In the fourth amplicon, RBBP5, a member of the RB pathway, may act as a novel oncogene in GBMs. Not all hCNAs contain known genes, which may suggest that other transcriptional and/or regulatory elements are the target for amplification. Regions with most frequent allelic loss, both in ODs and GBMs, resulted in a reduced expression of known tumor suppressor genes. We identified a homozygous deletion spanning the Pragmin gene in one sample, but direct sequencing of all coding exons in 20 other glioma samples failed to detect additional genetic changes. Finally, we screened for fusion genes by identifying aberrant 5,-3, expression of genes that lie over regions of a copy number change. A fusion gene between exon 11 of LEO1 and exon 10 of SLC12A1 was identified. Our data show that integrated genomic profiling can identify genes involved in tumor initiation, and/or progression and can be used as an approach to identify novel fusion genes. © 2010 Wiley-Liss, Inc. [source] Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic neviAGING CELL, Issue 4 2007Debdutta Bandyopadhyay Summary The retinoblastoma (RB)/p16INK4a pathway regulates senescence of human melanocytes in culture and oncogene-induced senescence of melanocytic nevi in vivo. This senescence response is likely due to chromatin modifications because RB complexes from senescent melanocytes contain increased levels of histone deacetylase (HDAC) activity and tethered HDAC1. Here we show that HDAC1 is prominently detected in p16INK4a -positive, senescent intradermal melanocytic nevi but not in proliferating, recurrent nevus cells that localize to the epidermal/dermal junction. To assess the role of HDAC1 in the senescence of melanocytes and nevi, we used tetracycline-based inducible expression systems in cultured melanocytic cells. We found that HDAC1 drives a sequential and cooperative activity of chromatin remodeling effectors, including transient recruitment of Brahma (Brm1) into RB/HDAC1 mega-complexes, formation of heterochromatin protein 1, (HP1,)/SUV39H1 foci, methylation of H3-K9, stable association of RB with chromatin and significant global heterochromatinization. These chromatin changes coincide with expression of typical markers of senescence, including the senescent-associated ,-galactosidase marker. Notably, formation of RB/HP1, foci and early tethering of RB to chromatin depends on intact Brm1 ATPase activity. As cells reached senescence, ejection of Brm1 from chromatin coincided with its dissociation from HP1,/RB and relocalization to protein complexes of lower molecular weight. These results provide new insights into the role of the RB pathway in regulating cellular senescence and implicate HDAC1 as a likely mediator of early chromatin remodeling events. [source] Molecular footprints of human lung cancer progressionCANCER SCIENCE, Issue 3 2004Jun Yokota Lung cancer is the leading cause of cancer-related death in the world. To understand the molecular processes and pathways of, and contributing factors to lung cancer progression, genetic alterations in various progression stages of lung cancer cells have been studied, since these alterations can be regarded as molecular footprints representing the individual processes of multistage lung carcinogenesis. The results indicate that defects in both the p53 and RB/p16 pathways are essential for the malignant transformation of lung epithelial cells. Several other genes, such as K- ras, PTEN and MYO18B, are genetically altered less frequently than p53 and RB/p16 in lung cancer cells, suggesting that alterations in these genes are associated with further malignant progression or unique phenotypes in a subset of lung cancer cells. However, it is still unclear what genes control the metastatic potential of lung cancer cells. Further analyses of molecular footprints in lung cancer cells, in particular in the cells of metastatic sites, will give us valuable information to fully understand the process of lung cancer progression, and to find novel ways of controlling it. Molecular footprints at the sites of p53 mutations and p16 deletions further indicate that DNA repair activities for G:C to T:A transversion and non-homologous end-joining of DNA double-strand breaks play important roles in the accumulation of genetic alterations in lung cancer cells. Thus, identification of environmental as well as genetic factors inducing or suppressing the occurrence of such alterations would be a clue to find novel ways of lung cancer prevention. [source] Abnormal Expression of p16INK4a, Cyclin D1, Cyclin-Dependent Kinase 4 and Retinoblastoma Protein in Gastric Carcinomas,JOURNAL OF SURGICAL ONCOLOGY, Issue 1 2008Ichiro Kishimoto MD Abstract Background and Objectives The p16INK4a (p16), cyclin D1, cyclin-dependent kinase (CDK) 4 and retinoblastoma (Rb) genes are components of the Rb pathway that controls the G1-S checkpoint of the cell cycle. The aim of this study was to assess the relationship between their abnormalities and clinicopathological features in gastric carcinomas. Mehtods Immunohistochemical analysis of the encoded proteins was performed on a series of 158 cases. Results Loss of p16/Rb protein (pRb) expression and overexpression of cyclin D1/CDK4 were observed in 49%/40% and 37%/37% of gastric carcinomas, respectively. At least 1 of these abnormalities was found in 86% of the cases and a positive correlation was noted between p16 and pRb (P,=,0.009). Cyclin D1 (P,=,0.042) and CDK4 (P,=,0.008) overexpession was inversely associated with lymph node metastasis and depth of invasion, respectively. Loss of pRb expression was more frequently in diffuse type lesions than in the intestinal type (P,=,0.022). The patients with p16+/pRb,/cyclin D1,/CDK4, or p16,/pRb+/cyclin D1,/CDK4, tumors demonstrated particularly poor survival. With multivariate survival analysis, only depth of invasion and TNM stage could be proven as independent predictors. Conclusions The Rb pathway is disrupted in the vast majority of gastric carcinomas. This study also identified specific immunohistochemical marker profiles for prognosis. J. Surg. Oncol. 2008;98:60,66. © 2008 Wiley-Liss, Inc. [source] Cellular lifespan and senescence signaling in embryonic stem cellsAGING CELL, Issue 6 2004Takumi Miura Summary Most mammalian cells when placed in culture will undergo a limited number of cell divisions before entering an unresponsive non-proliferating state termed senescence. However, several pathways that are activated singly or in concert can allow cells to bypass senescence at least for limited periods. These include the telomerase pathway required to maintain telomere ends, the p53 and Rb pathways required to direct senescence in response to DNA damage, telomere shortening and mitogenic signals, and the insulin-like growth factor , Akt pathway that may regulate lifespan and cell proliferation. In this review, we summarize recent findings related to these pathways in embryonic stem (ES) cells and suggest that ES cells are immortal because these pathways are tightly regulated. [source] BRD7, a novel bromodomain gene, inhibits G1,S progression by transcriptionally regulating some important molecules involved in ras/MEK/ERK and Rb/E2F pathwaysJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2004Jie Zhou Bromodomain is a 110 amino acid domain. It is evolutionally conserved and is found in proteins strongly implicated in signal-dependent transcriptional regulation. BRD7 is a novel bromodomain gene and it is downexpressed in nasopharyngeal carcinoma (NPC) biopsies and cell lines; its function is poorly understood. In the present study, tet-on inducible expression system was used to investigate the role of BRD7 in cell growth and cell cycle progression. We found that ectopic expression of BRD7 in NPC cells inhibited cell growth and cell cycle progression from G1 to S. We further performed cell cycle cDNA array to screen potential transcriptional targets of BRD7 in cell cycle. Thirteen important signaling molecules, mainly implicated in ras/MEK/ERK and Rb/E2F pathways, were differentially expressed by induction of BRD7. Moreover, we observed that BRD7 could regulate the promoter activity of E2F3, one of its targets. Taken together, the present study indicated that BRD7 inhibited G1,S progression by transcriptionally regulating some important molecules involved in ras/MEK/ERK and Rb/E2F pathways and suggested that BRD7 may present a promising candidate of NPCÔ associated tumor suppressor gene. © 2004 Wiley-Liss, Inc. [source] | |||||||||||||