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Oncogenesis
Selected AbstractsC-myc as a modulator of renal stem/progenitor cell populationDEVELOPMENTAL DYNAMICS, Issue 2 2009Martin Couillard Abstract The role of c - myc has been well-studied in gene regulation and oncogenesis but remains elusive in murine development from midgestation. We determined c - myc function during kidney development, organogenesis, and homeostasis by conditional loss of c - myc induced at two distinct phases of nephrogenesis, embryonic day (e) 11.5 and e17.5. Deletion of c - myc in early metanephric mesenchyme (e11.5) led to renal hypoplasia from e15.5 to e17.5 that was sustained until adulthood (range, 20,25%) and, hence, reproduced the human pathologic condition of renal hypoplasia. This phenotype resulted from depletion of c - myc,positive cells in cap mesenchyme, causing a ,35% marked decrease of Six2- and Cited1-stem/progenitor population and of proliferation that likely impaired self-renewal. By contrast, c - myc loss from e17.5 onward had no impact on late renal differentiation/maturation and/or homeostasis, providing evidence that c - myc is dispensable during these phases. This study identified c - myc as a modulator of renal organogenesis through regulation of stem/progenitor cell population. Developmental Dynamics 238:405,414, 2009. © 2009 Wiley-Liss, Inc. [source] Frequent multiple c-ki- ras oncogene activation in pancreatic juice from patients with benign pancreatic cystsDIGESTIVE ENDOSCOPY, Issue 2 2001Akihiko Nakaizumi Background: We detected benign pancreatic cysts in more than half of 12 cases of in situ pancreatic cancer. A few investigators, having detected K- ras mutation in pancreatic juice before the clinical diagnosis of pancreatic cancer, have suggested that this mutation might be an early event in pancreatic oncogenesis. Therefore, in the present study, we evaluated whether benign pancreatic cysts are a precancerous condition as reflected by K- ras mutation in pancreatic juice. Methods: Pancreatic juice was collected through endoscopic cannulation of the pancreatic duct. Analysis of the mutations was performed using the polymerase chain reaction,preferential homoduplex formation assay. Results: The frequencies and types of K- ras point mutations and the rate of multiplicity of K- ras mutations in patients with benign pancreatic cyst were the same as those with pancreatic cancer. Conclusions: Multiple K- ras codon 12 mutations in the pancreatic juice of patients with benign pancreatic cysts are present as frequently as those with pancreatic cancer. These results indicate that patients with benign cysts may be at a high-risk for the development of pancreatic cancer. [source] Determination of DNA methylation by COBRA: A comparative study of CGE with LIF detection and conventional gel electrophoresisELECTROPHORESIS, Issue 17 2009Simon Goedecke Abstract DNA methylation as an epigenetic modification of the human genome is under emphatic investigation. Several studies have demonstrated a role of DNA methylation in oncogenesis. In conjunction with histone modifications, DNA methylation may cause the formation of heterochromatin and thus mediate the inactivation of gene transcription. It is important to develop methods that allow for an accurate quantification of the amount of DNA methylation in particular DNA regions, to gain information concerning the threshold of methylation levels necessary for gene inactivation. In this article, a CGE method with on-column LIF detection using SYBR Green is compared with a conventional slab-gel electrophoresis. We thus investigate the validity to analyze DNA methylation in the samples of a combined bisulfite restriction analysis. It is demonstrated that CGE is superior to gel electrophoresis in means of linearity, precision, accuracy, automatization (high throughput), and sample consumption. However, gel electrophoresis is easier to perform (simple devices, no PC usage), and the running costs are comparatively low. A further advantage of CGE is the sparse use of toxic compounds (MeOH and SYBR Green), whereas gel electrophoresis is performed in polyacrylamide gels with ethidium bromide staining. [source] Vinexin , regulates the phosphorylation of epidermal growth factor receptor on the cell surfaceGENES TO CELLS, Issue 9 2006Masaru Mitsushima Epidermal growth factor (EGF) regulates various cellular events, including proliferation, differentiation, migration and oncogenesis. In this study, we found that exogenous expression of vinexin , enhanced the phosphorylation of 180-kDa proteins in an EGF-dependent manner in Cos-7 cells. Western blot analysis using phospho-specific antibodies against EGFR identified EGFR as a phosphorylated 180-kDa protein. Vinexin , did not stimulate the phosphorylation of EGFR but suppressed the dephosphorylation, resulting in a sustained phosphorylation. Mutational analyses revealed that both the first and third SH3 domains were required for a sustained phosphorylation of EGFR. Small interfering RNA-mediated knockdown of vinexin , reduced the phosphorylation of EGFR on the cell surface in HeLa cells. The sustained phosphorylation of EGFR induced by vinexin , was completely abolished by adding the EGFR-specific inhibitor AG1478 even after EGF stimulation, suggesting that the kinase activity of EGFR is required for the sustained phosphorylation induced by vinexin ,. We also found that E3 ubiquitin ligase c-Cbl is a binding partner of vinexin , through the third SH3 domain. Expression of wild-type vinexin , but not a mutant containing a mutation in the third SH3 domain decreased the cytosolic pool of c-Cbl and increased the amount of membrane-associated c-Cbl. Furthermore, over-expression of c-Cbl suppressed the sustained phosphorylation of EGFR induced by vinexin ,. These results suggest that vinexin , plays a role in maintaining the phosphorylation of EGFR on the plasma membrane through the regulation of c-Cbl. [source] Identification of a novel BTB-zinc finger transcriptional repressor, CIBZ, that interacts with CtBP corepressorGENES TO CELLS, Issue 9 2005Nobuhiro Sasai The transcriptional corepressor C-terminal binding protein (CtBP) is thought to be involved in development and oncogenesis, but the regulation of its corepressor activity is largely unknown. We show here that a novel BTB-zinc finger protein, CIBZ (CtBP-interacting BTB zinc finger protein; a mouse ortholog of rat ZENON that was recently identified as an e-box/dyad binding protein), redistributes CtBP to pericentromeric foci from a diffuse nuclear localization in interphase cells. CIBZ physically associates with CtBP via a conserved CtBP binding motif, PLDLR. When heterologously targeted to DNA, CIBZ represses transcription via two independent repression domains, an N-terminal BTB domain and a PLDLR motif-containing RD2 region, in a histone deacetylase-independent and -dependent manner, respectively. Mutation in the PLDLR motif abolishes the CIBZ-CtBP interaction and transcriptional repression activity of RD2, but does not affect the repression activity of the BTB domain. Furthermore, this PLDLR-mutated CIBZ cannot target CtBP to pericentromeric foci, although it is localized to the pericentromeric foci itself. These results suggest that at least one repression mechanism mediated by CIBZ is recruitment of the CtBP/HDAC complex to pericentromeric foci, and that CIBZ may regulate pericentromeric targeting of CtBP. [source] Genotypic and phenotypic classification of cancer: How should the impact of the two diagnostic approaches best be balanced?GENES, CHROMOSOMES AND CANCER, Issue 9 2010Petter Brandal Neoplastic tumors are traditionally named based on their differentiation (i.e., which normal cells and tissues they resemble) and bodily site. In recent years, knowledge about the genetic basis of tumorigenesis has grown rapidly, and the new information has in several instances been incorporated into the very definition of cancerous entities. The proper contribution of the diseases' phenotype and genotype to what they are called and how they are delineated from one another has rarely been subjected to explicit reasoning, however, nor is it often made clear whether existing naming practices are founded on ontological or utilitarian grounds. We look at several examples of how the new cytogenetic and molecular genetic understanding of tumorigenesis has impacted oncological nomenclature in a significant manner, but also at counterexamples where no similar change has taken place. In all likelihood, more and more neoplastic diseases will in the future be defined and named based on their pathogenesis rather than their phenotype, not least because effective and specific drug therapies directed against the molecular change at the very heart of oncogenesis will increasingly become available. The fact that this shift in emphasis is primarily guided by utilitarian considerations rather than any perception of acquired genetic changes as somehow being more ontologically "profound" or "important" in tumorigenesis, is as it should be; both the phenotype and the genotype of tumors are key parameters across most of oncology and are likely to be retained as the basis of coexisting disease classifications for as long as we can foresee. © 2010 Wiley-Liss, Inc. [source] WIF1, an inhibitor of the Wnt pathway, is rearranged in salivary gland tumors,GENES, CHROMOSOMES AND CANCER, Issue 3 2007Lurdes Queimado Chromosome rearrangements involving 12q13-15 are frequent among several tumors, including pleomorphic adenomas. The common molecular target for these aberrations is the HMGA2 gene, but various fusion partners of HMGA2 have been reported in tumors. Here we report the identification of the WNT inhibitory factor 1 (WIF1) gene as a novel HMGA2 fusion partner in a salivary gland pleomorphic adenoma. In normal salivary gland tissue WIF1 is expressed at a high level and HMGA2 is not expressed. However, in the pleomorphic adenoma expressing the HMGA2/WIF1 fusion transcript, we observed re-expression of HMGA2 wild-type transcripts and very low levels of WIF1 expression. These data suggest a possible synergistic effect between upregulation of HMGA2 and downregulation of WIF1. We screened 13 additional benign and malignant salivary gland tumors and detected WIF1 rearrangement in one out of two carcinomas ex-pleomorphic adenoma analyzed. In this malignant tumor, the rearrangement of one WIF1 allele coexists with loss of the other allele, a classic signature of a tumor suppressor gene. WIF1 is an antagonist of the Wnt signaling pathway, which plays a critical role in human cancer. In transgenic mouse models, Wnt activation leads to a high frequency of benign and malignant salivary gland tumors. To our knowledge, this is the first report suggesting that WIF1 is a recurrent target in human salivary gland oncogenesis and that downregulation of WIF1 plays a role in the development and/or progression of pleomorphic adenomas. © 2006 Wiley-Liss, Inc. [source] Role of hepatitis C virus proteins (C, NS3, NS5A) in hepatic oncogenesisHEPATOLOGY RESEARCH, Issue 1 2008Aldona Kasprzak In recent years, the effects of hepatitis C virus (HCV) proteins on hepatocarcinogenesis have undergone intense investigations. The potentially oncogenic proteins include at least three HCV proteins: core (C) protein, NS3, and NS5A. Several authors indicated relationships between subcellular localization, concentration, a specific molecular form of the proteins (full length, truncated, phosphorylated), the presence of specific domains (the nuclear localization signal homologous to e.g. Bcl-2) and their effects on the mechanisms linked to oncogenesis. The involvement of all the proteins has been described as being in control of the cell cycle, through interactions with key proteins of the process (p53, p21, cyclins, proliferating cell nuclear antigen), transcription factors, proto-oncogenes, growth factors/cytokines and their receptors, and proteins linked to the apoptotic process. Untilnow, the involvement of the core protein of HCV in liver carcinogenesis is the most recognized. One of the most common proteins affected by HCV proteins is the p53 tumor-suppressor protein. The p21/WAF1 gene is a major target of p53, and the effect of HCV proteins on the gene is frequently considered in parallel. The results of studies on the effects of HCV proteins on the apoptotic process are controversial. This work summarizes the information collected thus far in the field of HCV molecular virology and principal intracellular signaling pathways in which HCV oncogenic proteins are involved. [source] Hepatitis C virus and malignancyHEPATOLOGY RESEARCH, Issue 6 2007Arief Suriawinata Hepatitis C virus (HCV) is a hepatotropic virus that causes chronic hepatitis, fibrosis and cirrhosis. HCV is associated with the development of primary liver tumors, namely hepatocellular carcinoma, cholangiocarcinoma and lymphoma. This article reviews HCV-related malignancies, and their prevalence and probable oncogenesis. [source] Papillary carcinoma of the thyroid: difficult yet fascinating model of oncogenesis and tumour progressionHISTOPATHOLOGY, Issue 5 2004T J Stephenson No abstract is available for this article. [source] Pathology of lymphoma progressionHISTOPATHOLOGY, Issue 4 2001H K Müller-Hermelink Reflecting the stepwise process of oncogenesis, lymphomas may cumulatively develop a more aggressive phenotype during the course of disease, a process referred to as lymphoma progression. Although morphological, clinical and biological aspects of lymphoma progression do not always overlap, changes in lymphoma morphology frequently indicate alterations in the clinical and biological behaviour of the disease. Indolent and aggressive lymphomas in disease progression can either be clonally related or represent clonally unrelated neoplasms. We propose to use the term ,lymphoma progression' in a biological sense denoting only clonal development of and within a lymphoma entity. The term ,composite lymphoma' should be used as a merely descriptive morphological designation for different lymphoma entities in one individual irrespective of clonal relationship. Many types of aggressive B-cell non-Hodgkin's lymphomas and Hodgkin's lymphomas are reported to secondarily develop in lymphoma progression. Genetic changes associated with lymphoma progression frequently abrogate the differentiating effects of alterations occurring in indolent lymphomas, leading to increased cell proliferation. Within different lymphoma entities, high-risk disease variants mimicking lymphoma progression exist. [source] Central neurocytomas are genetically distinct from oligodendrogliomas and neuroblastomasHISTOPATHOLOGY, Issue 2 2000C Y K Tong Aims Central neurocytoma is a rare central nervous system tumour typically found in the lateral ventricles and at the septum pellucidum. Histologically, it resembles oligodendrogliomas and yet ultrastructurally, it shows neuronal differentiation. Its molecular oncogenesis is not known. The aim of this study was to examine whether major genetic events found in oligodendrogliomas and neuronal tumours, namely allelic deletions of chromosomes 1p and 19q and N-myc amplification, can be found in central neurocytomas. As there was one report describing gain of chromosome 7 in central neurocytomas, we also examined epidermal growth factor receptor (EGFR) amplification, as the EGFR gene is located at chromosome 7p. Methods and results Nine central neurocytomas and matched blood samples were examined for loss of heterozygosity (LOH) of 1p and 19q13.2,13.4 with 23 finely mapped microsatellite markers. N-myc amplification was studied by fluorescence in-situ hybridization using paraffin-embedded sections. EGFR amplification was tested for by differential PCR. Six of nine (67%) tumours showed LOH at one or more loci at 1p and 5/9 (56%) of cases showed LOH at 19q. However, common regions of deletion cannot be identified. The majority of informative markers are retained at 1p (84%) and 19q (86%). Only one tumour showed amplification of N-myc and none of the cases showed amplification of EGFR. Conclusion Central neurocytomas are genetically distinct from oligodendrogliomas, and chromosomes 1p and 19q probably do not play an important role in their pathogenesis. N-myc and EGFR amplification are rare. [source] Somatic microindels: analysis in mouse soma and comparison with the human germline,,HUMAN MUTATION, Issue 1 2007Kelly D. Gonzalez Abstract Microindels, defined as mutations that result in a colocalized microinsertion and microdeletion with a net gain or loss of between 1 and 50 nucleotides, may be an important contributor to cancer. We report the first comprehensive analysis of somatic microindels. Our large database of mutations in the lacI transgene of Big Blue® mice contains 0.5% microindels, 2.8% pure microinsertions, and 11.5% pure microdeletions. There appears to be no age, gender, or tissue-type specificity in the frequency of microindels. Of the independent somatic mutations that result in a net in-frame insertion or deletion, microindels are responsible for 13% of protein expansions and 6% of protein contractions. These in-frame microindels may play a crucial role in oncogenesis and evolution via "protein tinkering" (i.e., modest expansion or contraction of proteins). Four characteristics suggest that microindels are caused by unique mechanisms, not just simple combinations of the same mechanisms that cause pure microinsertions and pure microdeletions. First, microinsertions and microdeletions commonly occur at hotspots, but none of the 30 microindels are recurrent. Second, the sizes of the deletions and insertions in microindels are larger and more varied than in pure microdeletions and pure microinsertions. Third, microinsertions overwhelmingly repeat the adjacent base (97%) while the insertions in microindels do so only infrequently (17%). Fourth, analysis of the sequence contexts of microindels is consistent with unique mechanisms including recruitment of translesion DNA synthesis polymerases. The mouse somatic microindels have characteristics similar to those of human germline microindels, consistent with similar causative mechanisms in mouse and human, and in soma and germline. Hum Mutat 28(1), 69,80, 2007. Published 2006 Wiley-Liss, Inc. [source] Detection of endogenous lithium in neuropsychiatric disorders,a model for biological transmutationHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 1 2002Ravi Kumar Kurup Abstract The human hypothalmus produces an endogenous membrane Na+ -K+ ATPase inhibitor, digoxin. A digoxin induced model of cellular/neuronal quantal state and perception has been described by the authors. Biological transmutation has been described in microbial systems in the quantal state. The study focuses on the plasma levels of digoxin, RBC membrane Na+ -K+ ATPase activity, plasma levels of magnesium and lithium in neuropsychiatric and systemic disorders. Inhibition of RBC membrane Na+ -K+ ATPase activity was observed in most cases along with an increase in the levels of serum digoxin and lithium and a decrease in the level of serum Mg++. The generation of endogenous lithium would obviously occur due to biological transmutation from magnesium. Digoxin and lithium together can produce added membrane Na+ -K+ ATPase inhibition. The role of membrane Na+ -K+ ATPase inhibition in the pathogenesis of neuropsychiatric and systemic disorders is discussed. The inhibition of membrane Na+ -K+ ATPase can contribute to an increase in intracellular calcium and a decrease in magnesium, which can result in a defective neurotransmitter transport mechanism, mitochondrial dysfunction and apoptosis, defective golgi body function and protein processing dysfunction, immune dysfunction and oncogenesis. Copyright © 2002 John Wiley & Sons, Ltd. [source] Biscoclaurine alkaloid cepharanthine inhibits the growth of primary effusion lymphoma in vitro and in vivo and induces apoptosis via suppression of the NF-,B pathwayINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Naoko Takahashi-Makise Abstract Primary effusion lymphoma (PEL) is a unique and recently identified non-Hodgkin's lymphoma that was originally identified in patients with AIDS. PEL is caused by the Kaposi sarcoma-associated herpes virus (KSHV/HHV-8) and shows a peculiar presentation involving liquid growth in the serous body cavity and a poor prognosis. As the nuclear factor (NF)- ,B pathway is activated in PEL and plays a central role in oncogenesis, we examined the effect of a biscoclaurine alkaloid, cepharanthine (CEP) on PEL derived cell lines (BCBL-1, TY-1 and RM-P1), in vitro and in vivo. An methylthiotetrazole assay revealed that the cell proliferation of PEL cell lines was significantly suppressed by the addition of CEP (1,10 ,g/ml). CEP also inhibited NF- ,B activation and induced apoptotic cell death in PEL cell lines. We established a PEL animal model by intraperitoneal injection of BCBL-1, which led to the development of ascites and diffuse infiltration of organs, without obvious solid lymphoma formation, which resembles the diffuse nature of human PEL. Intraperitoneal administration of CEP inhibited ascites formation and diffuse infiltration of BCBL-1 without significant systemic toxicity in this model. These results indicate that NF- ,B could be an ideal molecular target for treating PEL and that CEP is quite useful as a unique therapeutic agent for PEL. © 2009 UICC [source] Transforming properties of TC-1 in human breast cancer: Interaction with FGFR2 and ,-catenin signaling pathwaysINTERNATIONAL JOURNAL OF CANCER, Issue 6 2007Zeng-Quan Yang Abstract Breast cancer development is associated with gene amplification and over expression that is believed to have a causative role in oncogenesis. Previous studies have demonstrated that over expression of TC-1(C8orf4) mRNA occurs in ,50% of breast cancer cell lines and primary tumor specimens. Here, we show that TC-1 has transforming properties in human mammary epithelial (HME) cells and its expression is mechanistically linked to FGFR signaling cascades. In vitro experiments demonstrate that TC-1 over expression mediates both anchorage-independent and growth factor-independent proliferation of HME cells. TC-1 was down regulated by the FGFR inhibitor PD173074 in the breast cancer cell line SUM-52 that also has an FGFR2 gene amplification and over expression. Furthermore, forced expression of FGFR2 in HME cells increased the level of expression of endogenous TC-1 mRNA. TC-1 has been implicated as a modulator of Wnt/,-catenin signaling in 293 cells and in gastric cancer cells. However, while we did find increased expression of a subset of ,-catenin target genes in TC-1 over expressing cells, we did not find an association of TC-1 with global expression of ,-catenin target genes in our cells. Taken together, our data suggest that TC-1 over expression is transforming and may link with the FGFR pathway in a subset of breast cancer. © 2007 Wiley-Liss, Inc. [source] HPV integration begins in the tonsillar crypt and leads to the alteration of p16, EGFR and c-myc during tumor formationINTERNATIONAL JOURNAL OF CANCER, Issue 7 2007Se-Heon Kim Abstract The prevalence of human papillomavirus (HPV) infection is high in the oropharyngeal mucosal regions, of which the tonsil is the most commonly affected. There may be a link between HPV and the pathogenesis of tonsillar cancer (TC), because of common anatomical characteristics between cervical and tonsillar cancer. We aimed to clarify whether HPV directly affects the oncogenesis and biologic behavior of TC by making a comparison between infection prevalence, physical status and viral loading numbers, and clinicopathologic prognostic factors. To compare HPV-related molecules between TC and tonsillitis (CFT), p16, survivin, HIF-1,, skp-1, cyclin A, cyclin B1, c-myc and EGFR were investigated. We observed a significant difference in HPV prevalence between 52 TCs and 69 CFTs (73.1% vs. 11.6%), and most of the HPVs were type 16 (87.2%) and nonepisomal (94.1%). Most TCs associated with HPV arose from the tonsillar crypts, and tended to be inverted and poorly differentiated. Compared with HPV-negative TC, HPV-positive TC showed a strong association with p16 overexpression (p < 0.0001), and an inverse association with EGFR amplification (p = 0.0478). HPV-16 integration status was strongly associated with c-myc amplification (p = 0.034) and HIF-1, overexpression (p = 0.022). HPV-16 integration could be directly related to tonsillar carcinogenesis initially in tonsillar crypts, followed by cell cycle aberration such as p16 overexpression related to the G1-S phase. © 2006 Wiley-Liss, Inc. [source] Gender-specific polygenic control of ethylnitrosourea-induced oncogenesis in the rat peripheral nervous systemINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006Bernd U. Koelsch Abstract The inbred BD rat strains constitute a model system for analysis of the genetic basis of susceptibility or resistance to the development of neural tumors, as they exhibit distinct strain-specific differences regarding the sensitivity to tumor induction by the alkylating carcinogen N -ethyl- N -nitrosourea (EtNU). Among the different BD strains, BDIX and BDIV rats, respectively, are either highly susceptible or entirely resistant to the development of EtNU-induced malignant schwannomas of the peripheral nervous system (PNS), predominantly of the trigeminal nerves. We have previously mapped one locus associated with susceptibility/resistance to schwannoma induction to the telomeric third of chromosome 10 (Mss1) in segregating (BDIX × BDIV) crosses. We report on the genetic mapping of 6 further loci controlling tumor incidence or survival time on chromosomes 1 (Mss2), 3 (Mss3), 6 (Mss4), 13 (Mss5) and 15 (Mss6) as well as on chromosome 10 (Mss7) close to the centromere. Interestingly, most of these loci mediate gender-specific effects of variable strength ranging from minor influences on tumor development to complete tumor resistance. The gender specificity is reflected by the fact that male (BDIX × BDIV) F2 rats exhibit a 2-fold higher incidence of EtNU-induced schwannomas than females as well as a shorter survival time. A number of human nervous system tumors too arise with a marked gender bias. Genes mediating gender-specific predisposition of developing malignant schwannomas in the rat may be relevant for the human individual risk of developing nervous system tumors. © 2005 Wiley-Liss, Inc. [source] Absence of acute apoptotic response to genotoxic carcinogens in p53 -deficient mice is associated with increased susceptibility to azoxymethane-induced colon tumoursINTERNATIONAL JOURNAL OF CANCER, Issue 4 2005Ying Hu Abstract Acute apoptotic response to genotoxic carcinogens (AARGC) might be important for controlling the consequences of mutational load in the colon. It has been shown to occur in parallel with activation of DNA repair mechanisms. Inadequate AARGC might allow development of mutated clones with the potential to progress to cancer. In this study, we tested if p53 levels were important for AARGC in the colon and whether defective AARGC was associated with increased risk for colorectal oncogenesis. Apoptosis was measured in colonic epithelium of mice from each p53 genotype (p53,/,, p53+/,, wild-type) without and 8 hr following a single injection of azoxymethane (AOM). To determine risk for carcinogen-induced colorectal cancer (CRC), groups of mice from each p53 genotype received 3 weekly injections of AOM and colons were examined for tumour 20 weeks later. Rates of spontaneous apoptosis in colon were not affected by p53 level. However, AARGC was absent in p53,/, mice and reduced by 50% in p53+/, mice (both p < 0.01) compared to wild-type mice. AOM induced tumours in 30% of wild-type mice (average multiplicity 1.0 tumours/mouse) compared to 72% of p53+/, mice (2.0 tumours/mouse, p < 0.01) and 100% of p53,/, mice (2.8 tumours/mouse, p < 0.01). Without AOM, significantly fewer mice in all groups had tumours. Rates of apoptosis in tumours were independent of p53 status. p53 dysfunction puts intestinal epithelia at increased risk of genotoxin-induced oncogenesis due to impairment of apoptotic response mechanisms. p53 levels do not appear, however, to be important for spontaneous apoptosis in normal epithelium or apoptosis in tumours. Subsequent studies are now warranted to test the converse, namely, that enhanced apoptotic response to carcinogen reduces risk for colorectal oncogenesis. © 2005 Wiley-Liss, Inc. [source] Deregulation of Stat5 expression and activation causes mammary tumors in transgenic miceINTERNATIONAL JOURNAL OF CANCER, Issue 4 2004Elena Iavnilovitch Abstract Members of the signal transducers and activators of transcription (Stat) family regulate essential cellular growth and survival functions in normal cells and have also been implicated in tumorigenesis. We have studied the potential role of Stat5 in mammary tumorigenesis by targeting Stat5 variants to the mammary gland of transgenic mice using regulatory sequences of the ,-lactoglobulin gene. Mammary-directed expression of the wild-type Stat5, constitutively activated Stat5 and carboxyl-terminally truncated dominant negative Stat5 forms resulted in mammary tumors with incidence rates of up to 22% and latency periods of 8,12 months. Undifferentiated carcinomas most frequently occurred in mice expressing the carboxyl-terminally truncated Stat5. The more differentiated papillary and micropapillary adenocarcinomas were primarily found in mice overexpressing the native and constitutively active transgenes. Higher levels of translation initiation factor 4E (eIF4E) and cyclin D1 expression but lower levels of activated Stat3 were found in tumors of mice expressing the constitutively active Stat5 when compared to mice expressing the wild-type or truncated forms. A higher expression of the estrogen receptor (ER,) was observed in carcinomas compared to other phenotypes. The ability of both forms of Stat5, the transactivating form and the dominant negative form, to participate in oncogenesis indicates that there is more than one mechanism by which Stat5 contributes to this process. The transactivation function of Stat5 is involved in the determination of tumors with a more differentiated phenotype. © 2004 Wiley-Liss, Inc. [source] Cyclin E expression in papillary thyroid carcinoma: Relation to stagingINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Jan Brzezi Abstract Cyclin E plays a pivotal role in the regulation of G1-S transition and relates to malignant transformation of the cells. However, the clinical significance of cyclin E expression in patients with papillary thyroid carcinoma (PTC) remains unknown. We examined by immunohistochemistry the expression of cyclin E in 41 resected PTCs in pathologic stages from pT1a to pT4 and analyzed its relation to clinicohistopathologic factors. The positive staining was divided into 3 grades: no expression if less than 10%, expression if 11,50% and overexpression if more than 50% of the nuclei of tumor cells were stained positively. Cylin E expressions were observed in 75.6% of analyzed PTCs but only 60% of papillary microcarcinomas (PMCs) were immunopositive for cyclin E expression. However, cyclin E staining was observed in 90.4% of PTCs in a group with TNM higher than pT1a. The staining index was significantly different between the PMCs and the rest of the cancers investigated (14.91% ± 14.4% vs. 34.03% ± 23.44%, respectively; p < 0.005) and we observed positive relation between the staining index and factor T of staging of PTCs. All the lymph node metastases coexisted with cyclin E expression and most, but not all, of them coexisted with cyclin E overexpression. These findings indicate that cyclin E may play a key role for the oncogenesis and biologic behavior of PTC. If our results are confirmed in a larger study, a high level of cyclin E expression may become a new prognostic marker for PTCs. © 2003 Wiley-Liss, Inc. [source] Expression of PAX 3 alternatively spliced transcripts and identification of two new isoforms in human tumors of neural crest originINTERNATIONAL JOURNAL OF CANCER, Issue 2 2004Craig J. Parker Abstract The developmental gene PAX 3 is expressed in the early embryo in developing muscle and elements of the nervous system, including the brain. Since no one has investigated the expression of the isoforms of PAX 3 in the neuroectodermal tumors melanoma and small cell lung cancer (SCLC), we have carried out a comprehensive screening for the expression of the isoforms PAX 3a,e using RT-PCR in human melanoma cell lines, primary human ocular and secondary cutaneous melanomas. We have identified 2 new isoforms of PAX 3, g and h, which we have isolated, cloned and sequenced. Sets of primers for each isoform were designed and their specificity was confirmed by sequence analysis of the products. The isoforms PAX 3a,e were detected in all human cutaneous melanoma cell lines (8/8), but only PAX 3c (1/2) and PAX 3d (2/2) in ocular melanoma cell lines. The same PAX 3 isoforms were detected in more than 80% of human cutaneous melanomas: PAX 3a and b (15/17), PAX 3c (14/17), PAX 3d (16/17) and PAX 3e (15/17). In contrast the results for 7 SCLC cell lines were PAX 3a (0/7), PAX 3b (1/7), PAX 3c (3/7), PAX 3d (6/7), PAX 3e (2/7); 8/8 cutaneous melanoma cell lines and 8/8 ocular melanoma tissues, together with 14/17 cutaneous melanoma tissues screened, expressed the new isoform PAX 3g. All 8 cutaneous melanoma cell lines expressed PAX 3h, but it was not detectable in any of the tumor tissues (0/20). Neither of the 2 ocular melanoma cell lines expressed the 2 new isoforms. Comparison of the different amplicon staining intensities on a gel suggests that PAX 3c and PAX 3d are the predominant transcripts expressed, with relatively low expression of PAX 3e and PAX 3h. We propose that these and the 2 new isoforms we have discovered may be important in oncogenesis and differential diagnosis of melanomas or SCLC. © 2003 Wiley-Liss, Inc. [source] Small interfering RNA (siRNA) inhibits the expression of the Her2/neu gene, upregulates HLA class I and induces apoptosis of Her2/neu positive tumor cell linesINTERNATIONAL JOURNAL OF CANCER, Issue 1 2004Aniruddha Choudhury Abstract Silencing of a specific mRNA using double stranded RNA oligonucleotides represents one of the newest technologies for suppressing a specific gene product. Small interfering RNA (siRNA) are 21 nucleotides long, double stranded RNA fragments that are identical in sequence to the target mRNA. We designed 3 such siRNA against the Her2/neu (HER2) gene. The HER2 gene is known to play an important role in the oncogenesis of several types of cancers, such as breast, ovarian, colon and gastric cancers. Introduction of the siRNA into HER2 positive tumor lines in vitro greatly reduced the cell surface expression of the HER2 protein. Concurrently, a range of effects on cell physiology, such as growth inhibition or apoptosis, was observed. The expression of HLA class I was observed to be upregulated when HER2 was silenced with siRNA. Treatment of SKBr3 and MCF7/HER2 tumor cell lines with the HER2 siRNA resulted in growth arrest of cells in the late G1/S-phase. Our results suggest that siRNA may be an effective method of abrogating the effect of HER2 in tumorigenesis. © 2003 Wiley-Liss, Inc. [source] Melatonin: therapeutic and clinical utilizationINTERNATIONAL JOURNAL OF CLINICAL PRACTICE, Issue 5 2007A. Altun Summary Melatonin, acting through melatonin receptors, is involved in numerous physiological processes including circadian entrainment, blood pressure regulation, oncogenesis, retinal physiology, seasonal reproduction, ovarian physiology, immune function and most recently in inducing osteoblast differentiation. Moreover, melatonin was proved to be a potent-free radical scavenger and a broad-spectrum antioxidant. More research is required into the effects of therapeutically modulating the melatoninergic system on circadian haemodynamics and rhythm under varying physiopathological conditions and the possible impact on morbidity and mortality in humans. [source] Urethral ,recurrence' found 14 years after radical cystectomyINTERNATIONAL JOURNAL OF UROLOGY, Issue 7 2004STEVEN SORSCHER Abstract We report a case of transitional cell urethral cancer diagnosed 14 years after radical cystectomy. Traditionally, in the postcystectomy setting, these cancers have been referred to as ,recurrences'. We review the biological models for the oncogenesis of these cancers and propose that they are typically a result of a field cancerization effect, rather than being derived from the same clone responsible for the original urothelial tumor. [source] INK4 proteins, a family of mammalian CDK inhibitors with novel biological functionsIUBMB LIFE, Issue 7 2007Eduardo T. Cánepa Abstract The cyclin D-Cdk4-6/INK4/Rb/E2F pathway plays a key role in controlling cell growth by integrating multiple mitogenic and antimitogenic stimuli. The members of INK4 family, comprising p16INK4a, p15INK4b, p18INK4c, and p19INK4d, block the progression of the cell cycle by binding to either Cdk4 or Cdk6 and inhibiting the action of cyclin D. These INK4 proteins share a similar structure dominated by several ankyrin repeats. Although they appear to be structurally redundant and equally potent as inhibitors, the INK4 family members are differentially expressed during mouse development. The striking diversity in the pattern of expression of INK4 genes suggested that this family of cell cycle inhibitors might have cell lineage-specific or tissue-specific functions. The INK4 proteins are commonly lost or inactivated by mutations in diverse types of cancer, and they represent established or candidate tumor suppressors. Apart from their capacity to arrest cells in the G1-phase of the cell cycle they have been shown to participate in an increasing number of cellular processes. Given their emerging roles in fundamental physiological as well as pathological processes, it is interesting to explore the diverse roles for the individual INK4 family members in different functions other than cell cycle regulation. Extensive studies, over the past few years, uncover the involvement of INK4 proteins in senescence, apoptosis, DNA repair, and multistep oncogenesis. We will focus the discussion here on these unexpected issues. iubmb Life, 59: 419-426, 2007 [source] Applications of Sleeping Beauty transposons for nonviral gene therapyIUBMB LIFE, Issue 6 2007Hanzhong Liu Abstract Virus-based gene therapy has advanced to clinical trials; however, this approach may result in serious adverse events including oncogenesis and the possibility of triggering fatal immune responses. Nonviral gene delivery approaches have a better safety profile, but their in vivo application has been largely limited in the past due to their inefficient delivery into cells and lack of stable chromosomal integration that is necessary for long-term therapeutic benefit. However, recent advances suggest that the use of Sleeping Beauty transposons, a novel integrating nonviral vector system, are capable of achieving long-lasting therapeutic levels of transgene expression in preclinical settings. These observations and other ongoing relevant studies may unlock the therapeutic potential of nonviral gene therapy for human diseases. iubmb Life, 59: 1 - 6, 2007 [source] KEYNOTE ADDRESS Ku80-deletion causes early ageing and suppresses cancerJOURNAL OF ANIMAL PHYSIOLOGY AND NUTRITION, Issue 2 2009P. Hasty Ageing is widespread cellular decline resulting in a loss of fitness that is both pleiotropic and stochastic and influenced by both genetics and environment. As a result the fundamental underling causes of ageing are diverse and controversial. One potential ageing target is nuclear DNA, as it is a permanent blueprint that controls cellular processes. Thus, DNA replication and genome maintenance are highly regulated events that ensure faithful reproduction and maintenance of the blueprint and these pathways assure sufficient longevity for reproduction and survival of the species. As a consequence, imperfections or defects in maintaining the genome may contribute to ageing. Therefore, genome maintenance pathways are longevity-assurance mechanisms that sustain an organism long enough to reproduce and propagate. Chief among these mechanisms are those that respond to damaged DNA. There are two basics responses to genomic damage: DNA repair and cell cycle checkpoints. Both are considered to be tumour suppressors and are categorized as either caretakers or gatekeepers, respectively. Interestingly, observations of human and mouse pre-mature ageing models suggest these anti-tumour pathways impact the ageing process. Caretakers suppress cancer by repairing DNA damage caused by defects in replication or by a variety of agents including endogenously produced reactive by-products of oxygen metabolism and exogenous agents naturally encountered in our environment. As a consequence DNA is subject to a variety of insults that cause a diverse range of lesions and phenotypic outcomes. There are many forms of DNA damage including base lesions and double-strand breaks (DSBs) with the latter being more toxic. Cancer-causing chromosomal rearrangements may result if DSBs are not repaired properly. Additionally, an accumulation of these rearrangements may contribute to ageing since they increase in some cell types as humans and mice age. Furthermore, early ageing models suggest that defects in repairing DSBs lead to early ageing in humans and mice. Non-homologous end joining (NHEJ) is an important pathway for repairing DNA DSBs and is considered a caretaker. The Ku heterodimer (composed of Ku70 and Ku80) binds to DNA ends to initiate NHEJ, and defects in either Ku70 or Ku80 lead to increased levels of DNA DSBs and chromosomal rearrangements, leading many to believe Ku is a caretaker. Ku-mutant mice display increased GCRs, but without increased cancer. Instead, these mice show early ageing and shortened life span. Thus, Ku's role as a caretaker is uncertain as the low cancer levels may be due to Ku80-deletion or, instead, the low cancer levels may simply be a consequence of the shortened life span that prohibits sufficient time for tumours to develop. Gatekeepers respond to DNA damage by halting the cell cycle long enough for the DNA to be repaired. If the damage is irreparable, gatekeepers induce either apoptosis or senescence. These responses are deleterious to the cell but protect the organism from cancer as one potential outcome of genetic mutations is uncontrolled proliferation. p53 is critical for checkpoints and is the best-known gatekeeper because it is mutated in over half of all cancers. In addition, p53 activity influences many aspects of the Ku-mutant phenotype suggesting that Ku-deletion leads to persistent p53-mediated responses and presenting the possibility that low cancer levels and early ageing are caused by elevated gatekeeper responses. Our hypothesis is that Ku-mutant mice exhibit low cancer levels and, perhaps, ageing due to persistent p53-mediated responses to inefficiently repaired DNA. To test this hypothesis, Ku80-mutant mice were crossed to cancer-prone mice with either non-functional or functional gatekeeper responses. Ku80-mutant mice were crossed to p53-mutant mice to determine if Ku80-deletion exacerbates oncogenesis when gatekeeper responses are diminished. Ku80-mutant mice deleted for p53 exhibit early onset and high levels of two forms of cancer: pro-B cell lymphoma and medulloblastoma, thus supporting the hypothesis. Ku80-mutant mice were also crossed to APCMIN mice to determine if Ku80-deletion ameliorates oncogenesis gatekeeper responses are intact. APCMIN mice exhibit high levels of intestinal adenomas and adenocarcinomas but have normal p53-mediated responses to DNA damage. APCMIN mice, deleted for Ku80, exhibit about 67% fewer tumours than APCMIN mice with Ku80. Thus, deletion of Ku80 suppresses tumour formation, again supporting the hypothesis. Ku80-mutant cells and tissues were tested for p53-mediated DNA damage responses, levels of DNA damage, and mutations. Ku80-mutant fibroblasts exhibit elevated levels of p53-mediated DNA damage responses that increase p21-mediated cellular senescence. In addition, there are elevated levels DNA damage as seen by increased 53BP1 foci and elevated levels of chromosomal rearrangements. Thus, these data support the hypothesis that Ku80-deletion reduces tumors by elevating DNA damage gatekeeper responses to inefficiently repaired DNA. These data also support the possibility that the Ku80-mutant ageing phenotype is also due to elevated gatekeeper responses. [source] Possible involvement in oncogenesis of a single base mutation in an internal ribosome entry site of Epstein,Barr nuclear antigen 1 mRNAJOURNAL OF MEDICAL VIROLOGY, Issue 4 2004Rika Endo Abstract It has been reported recently that the U leader exon located within the 5, untranslated region of Epstein,Barr nuclear antigen 1 (EBNA1) gene contains an internal ribosome entry site (IRES) element. Sequence analysis of the U leader exon was undertaken in samples from 19 patients with infectious mononucleosis and 19 patients with lethal lymphoproliferative diseases and in 15 spontaneously established lymphoblastoid cell lines. The sequence was conserved except for a single base substitution (T-C) at position 67,585. Although the mutation was detected in only one case of infectious mononucleosis, it was found in more than half of the lethal lymphoproliferative diseases and all lymphoblastoid cell lines. The results suggest that a mutation in the IRES element affects EBNA1 gene expression at the translational level and provides Epstein,Barr virus (EBV)-infected cells with a growth advantage, leading to immortalization of cells in vitro and to the development of lethal lymphoproliferative diseases in vivo. J. Med. Virol. 72:630,634, 2004. © 2004 Wiley-Liss, Inc. [source] The cell migration protein Grb7 associates with transcriptional regulator FHL2 in a Grb7 phosphorylation-dependent mannerJOURNAL OF MOLECULAR RECOGNITION, Issue 1 2009Sharareh Siamakpour-Reihani Abstract Grb7 is an adaptor molecule that can mediate signal transduction from multiple cell surface receptors to various downstream signaling pathways. Grb7, along with Grb10 and Grb14, make up the Grb7 protein family. This protein family has been shown to be overexpressed in certain cancers and cancer cell lines. Grb7 and a receptor tyrosine kinase (RTK), erbB2, are overexpressed in 20,30% of breast cancers. Grb7 overexpression has been linked to enhanced cell migration and metastasis, though the participants in these pathways have not been determined. In this study, we report that Grb7 interacts with four and half lim domains isoform 2 (FHL2), a transcription regulator with an important role in oncogenesis, including breast cancer. Additionally, in yeast 2-hybrid (Y2H) assays, we show that the interaction is specific to the Grb7 RA and PH domains. We have also demonstrated that full-length (FL) Grb7 and FHL2 interact in mammalian cells and that Grb7 must be tyrosine phosphorylated for this interaction to occur. Immunofluorescent microscopy demonstrates possible co-localization of Grb7 and FHL2. A model with supporting NMR evidence of Grb7 autoinhibition is proposed. Copyright © 2008 John Wiley & Sons, Ltd. [source] |