Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Molecular techniques are becoming increasingly important in the analysis of NHL, both for diagnostic purposes and in order to evaluate prognosis accurately. The increasing number of techniques available renders evaluation of their relative roles important and a review of their informativity in NHL at diagnosis timely. Molecular equivalents of chromosomal translocations generate either a qualitative change due to the expression of a chimaeric, relatively tumour specific, protein, such as the NPM-ALK associated with the t(2;5) in ALCL or a quantitative change in the extent, stage or site of expression of a full length protein, due to its juxtapositioning to and deregulation by an Ig or TCR gene. The latter represents errors of the somatic recombination process which lymphoid precursors undergo. In NHL, this category includes BCL1/CCND1, BCL2, BCL6 and MYC. The molecular characteristics, the functional consequences and the main clinical correlations of each of these abnormalities is reviewed. At diagnosis, immunological detection of the deregulated 'protooncogene' may well provide the simplest, most appropriate screening technique for CCND1 and NPM-ALK induced ALK expression. BCL6 abnormalities demonstrate similarities to BCL2 and MYC and a combination of immunophenotypic, FISH, Southern blot and PCR techniques are useful in their characterization. For the approximately 50% of NHL without one of the above markers, identification of a clonal Ig or TCR rearrangement can provide a useful 'pan' B or T molecular equivalent, provided that the limitations of the detection techniques are appreciated. Appropriate use of these techniques will transform our ability to classify, stratify and eventually treat in a risk adapted manner, patients with NHL.
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PMID:Practical role of molecular diagnostics in non-Hodgkin's lymphomas. 913 11

It has now been clearly established that quantitative immunohistochemical methods applied to tumour angiogenesis under suitable quality control conditions are a powerful prognostic tool for use in the initial assessment of breast carcinomas. Appropriate parameters for predicting the aggressiveness of tumours and their sensitivity to treatment are, however, still required. To determine whether the microvessel count (MVC) may serve to predict the chemotherapeutic response, a retrospective study was carried out on a series of 162 patients with breast carcinoma, who were all treated with the same standard adjuvant chemotherapy. Angiogenesis was assessed by performing CD31 immunostaining and MVC per mm2. Several other factors such as P53, ERBB2, BCL2, and Ki67 were also measured, and their prognostic value was compared with that of the MVC. The MVC was not found to be correlated with any of the other prognostic parameters, but turned out to be of great prognostic value whatever the threshold value chosen, which suggests that it is continuously valid at all levels. The median value of the MVC (43.5 per mm2) divided this series into two significantly different prognostic categories, in terms of both disease-free survival (P = 0.0002) and overall survival (P = 0.037). Univariate analysis showed that most of the parameters analysed were of prognostic value regarding the disease-free survival, namely grade (P = 0.029), mitotic index (P = 0.049), size (P = 0.015), oestrogen receptors (P = 0.022), progesterone receptors (P = 0.018), P53 (P = 0.0045), ERBB2 (P = 0.046), and Ki67 (P = 0.0008). As regards overall survival, grade and ERBB2 showed a loss of prognostic value. In multivariate analysis on disease-free survival, the MVC was the most accurate prognostic factor (RR = 2.64), followed by Ki67 (RR = 2.06) and P53 (RR = 1.69). With respect to overall survival, the MVC ranked third among the prognostic parameters analysed. Standard chemotherapy did not reduce the high prognostic value of the MVC performed on tumour angiogenesis. This suggests that the MVC may predict the degree of resistance to chemotherapy. Patients with high levels of angiogenesis, particularly node-negative patients, might therefore be able to benefit from adjuvant therapy of another kind.
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PMID:Angiogenesis as a prognostic marker in breast carcinoma with conventional adjuvant chemotherapy: a multiparametric and immunohistochemical analysis. 960

Abnormalities involving the 14q32 region are recurrent chromosomal changes in plasma cell malignancies. Recent preliminary molecular analyses found IGH rearrangements in almost 100% of human myeloma cell lines and in 75% of patients. However, no systematic study analyzing the nature of the partner chromosomal regions have been reported thus far. To define the exact incidence of illegitimate IGH rearrangements and the respective incidence of partner genes cloned to date, we analyzed 141 patients with either multiple myeloma (MM, n = 127) or primary plasma cell leukemia (PCL, n = 14) using fluorescence in situ hybridization. The overall incidence of illegitimate recombinations was 57% (80 of 141 patients). Analysis of this incidence according to Durie and Salmon stage, patients' status, i.e., MM versus primary PCL and diagnosis versus relapse, immunoglobulin type and subtype, and beta2-microglobulin value, did not show any correlation. To analyze the nature of the partner chromosomal region, we selected probes specific for the following genes: FGFR3 (4p16), MYC (8q24), CCND1 (11q13), MAF (16q23), and BCL2 (18q21). These probes, combined with differentially labeled 14q32 probes, were used for dual-color fluorescence in situ hybridization on interphase plasma cells. Among the 80 patients with illegitimate IGH rearrangement, we identified 23 IGH-CCND1 fusion cases [i.e., t(11;14)], 17 IGH-FGFR3 fusion cases [i.e., t(4;14)], 3 IGH-MYC fusion cases [i.e., t(8;14)], and only one IGH-MAF fusion case. No IGH-BCL2 fusion case was detected. In 37 of 80 patients, none of these partner genes was involved. Analysis of cases with specific translocations according to their bioclinical features at diagnosis did not show any correlation. This study demonstrated that CCND1 and FGFR3 genes are involved together in about 50% of MM and primary PCL patients with illegitimate IGH rearrangements.
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PMID:High incidence of translocations t(11;14)(q13;q32) and t(4;14)(p16;q32) in patients with plasma cell malignancies. 986 13

Proliferation, differentiation, and apoptosis are tightly regulated during hematopoiesis, allowing amplification along specific lineages while preventing excessive proliferation of immature cells. The MCL1 member of the BCL2 family is up-regulated during the induction of monocytic differentiation (approximately 10-fold with 12-O-tetradecanoylphorbol 13-acetate (TPA)). MCL1 has effects similar to those of BCL2, up-regulation promoting viability, but differs from BCL2 in its rapid inducibility and its pattern of expression. Nuclear factors that regulate MCL1 transcription have now been identified, extending the previous demonstration of signal transduction through mitogen-activated protein kinase. A 162-base pair segment of the human MCL1 5'-flank was found to direct luciferase reporter activity, allowing approximately 10-fold induction with TPA that was suppressible upon inhibition of the extracellular signal-regulated kinase (ERK) pathway. Serum response factor (SRF), Elk-1, and Sp1 bound to cognate sites within this segment, SRF and Elk-1 acting coordinately to affect both basal activity and TPA inducibility, whereas Sp1 affected basal activity only. Thus, the mechanism of the TPA-induced increase in MCL1 expression seen in myelomonocytic cells at early stages of differentiation involves signal transduction through ERKs and transcriptional activation through SRF/Elk-1. This finding provides a parallel to early response genes (e.g. c-FOS and EGR1) that affect maturation commitment in these cells and therefore suggests a means through which enhancement of cell viability may be linked to the induction of differentiation.
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PMID:Regulation of MCL1 through a serum response factor/Elk-1-mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation. 988 May 63

The expression of cytotoxic granule-associated proteins has been reported in some T-cell or natural killer (NK)-cell lymphomas of mostly extranodal origin, but rarely of nodal origin except for anaplastic large cell lymphoma (ALCL) and Hodgkin's disease (HD). This study analyzed 66 nodal lymphomas expressing T-cell intracellular antigen-1 (TIA-1) and/or granzyme B to characterize the clinicopathologic spectrum of these neoplasms. Four main groups could be delineated. The first group consisted of p80/anaplastic lymphoma kinase (ALK)-positive ALCL (n = 35). The patients were 2 to 62 years of age (median age, 16 years), and the lymphomas pursued a relatively indolent clinical course. The tumors were phenotypically of either T- or null-cell type with constant expression of CD30, epithelial membrane antigen (EMA), and p80/ALK, but not CD15 or BCL2. None harbored Epstein-Barr virus (EBV). The second group consisted of peripheral T/NK-cell lymphoma, the nodal high-grade cytotoxic type (n = 13). The patients were 29 to 72 years in age (median age, 55 years), and the tumors pursued an aggressive clinical course. The tumors often showed pleomorphic, anaplastic, or centroblastoid morphology, and were featured by either EBV association or CD56 expression. The third group consisted of peripheral T-cell lymphoma, of the nodal low-grade cytotoxic type (n = 8). The patients, three men and five women, were 31 to 75 years old (median age, 61 years). Notably, six of them exhibited lymphoepithelioid (Lennert's) lymphoma. The fourth group consisted of cytotoxic Hodgkin's-like ALCL/HD (n = 10), included seven cases of Hodgkin's-like ALCL and three cases of HD, and was characterized by the presence of Reed-Sternberg cells and often the CD15+ phenotype. The patients were all men except for one woman, and they ranged in age from 24 to 84 years (median age, 62 years). The link among these four groups was reinforced by the presence of a highly characteristic large cell with horseshoelike or reniform nuclei-the frequent expression of CD30 and EMA-and the often lack of T-cell receptor-alphabeta. In this series, the expression of p80/ALK and CD56 was also associated with favorable and poor prognoses respectively (p<0.001, log-rank test).
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PMID:Nodal cytotoxic lymphoma spectrum: a clinicopathologic study of 66 patients. 1097 9

The Raf oncoprotein plays critical roles in the transmission of mitogenic signals from cytokine receptors to the nucleus. There are three Raf family members: A-Raf, B-Raf and Raf-1. Conditionally active forms of the Raf proteins were created by ligating N-terminal truncated activated forms to the estrogen-receptor (ER) hormone-binding domain resulting in beta-estradiol-inducible constructs. We introduced these chimeric deltaRaf:ER oncoproteins into the murine FDC-P1 hematopoietic cell line. Two different types of cells were recovered after drug selection in medium containing either cytokine or beta-estradiol: (1) cytokine-dependent cells that expressed the deltaRaf:ER oncoproteins; and (2) Raf-responsive cells that grew in response to the deltaRaf:ER oncoprotein. Depending upon the particular deltaRaf:ER oncoprotein, cytokine-dependent cells were recovered 10(3) to 10(5) times more frequently than Raf-responsive cells. To determine whether BCL2 could synergize with the deltaRaf:ER oncoproteins and increase the frequency of cytokine-independent cells, cytokine-dependent deltaRaf:ER-expressing cells were infected with either a BCL2 containing retrovirus or an empty retroviral vector. BCL2 overexpression, by itself, did not relieve cytokine dependency of the parental cell line. However, BCL2 overexpression increased the frequency of Raf-responsive cells approximately five- to 100-fold. Cytokine-dependent deltaRaf:ER-infected cells entered the G1 phase of the cell cycle after cytokine withdrawal and entered S phase only after cytokine addition. Raf-responsive deltaRaf:ER cells entered the G1 phase of the cell cycle after estrogen deprivation and re-entered the cell cycle after addition of either IL-3 or the estrogen receptor antagonist tamoxifen which activates the deltaRaf:ER constructs. Expression of the BCL2 oncoprotein often delayed the exit from the S and G2/M phases demonstrating the protective effects BCL2 provided to these Raf and BCL2 infected cells. The deltaRaf:ER cells expressed the deltaRaf:ER proteins and downstream MEK and ERK activities after beta-estradiol treatment. Raf-responsive cells that were also infected with BCL2 expressed higher levels of BCL2 than the cells that were not infected with BCL2. Thus BCL2 can synergize with the activated Raf in the abrogation of cytokine dependency of certain hematopoietic cells. These cells will be useful in furthering our understanding of the roles of the Raf and BCL2 oncoproteins in hematopoietic cell growth, cell cycle progression and prevention of apoptosis.
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PMID:Synergy between Raf and BCL2 in abrogating the cytokine dependency of hematopoietic cells. 1086 73

Transformations between epithelial and mesenchymal cells are widespread during normal development and adult disease, and transforming growth factor-beta1 (TGF-beta1) has been implicated in some of these phenotypic switches. Dysplastic kidneys are a common cause of chronic kidney failure in young children and result from perturbed epithelial-mesenchymal interactions. In this study, we found that components of the TGF-beta1 axis were expressed in these malformations: TGF-beta1 mRNA and protein were up-regulated in dysplastic epithelia and surrounding mesenchymal cells, whereas TGF-beta receptors I and II were expressed in aberrant epithelia. We generated a dysplastic kidney epithelial-like cell line that expressed cytokeratin, ZO1, and MET, and found that exogenous TGF-beta1 inhibited proliferation and decreased expression of PAX2 and BCL2, molecules characterizing dysplastic tubules in vivo. Furthermore, addition of TGF-beta1 specifically induced morphological changes compatible with a shift to a mesenchymal phenotype, accompanied by loss of ZO1 at cell borders and up-regulation of the mesenchymal markers alpha-smooth muscle actin and fibronectin. The descriptive and functional data presented in this report potentially implicate TGF-beta1 in the pathobiology of dysplastic kidneys and our results provide preliminary evidence that an epithelial-to-mesenchymal phenotypic switch may be implicated in a clinically important developmental aberration.
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PMID:Potential biological role of transforming growth factor-beta1 in human congenital kidney malformations. 1107 23

In a previous immunophenotypic molecular-based analysis it was shown that bcl2 over-expression characterizes the SS gene profile in addition to the non-random translocations. Here we show that the over-expression of an additional potentially antiapoptotic gene, the c-KIT gene, is associated with this tumour. Interestingly, whereas bcl2 over-expression appears to be restricted to the spindle cell tumoral component, c-kit mainly involves the epithelial component of biphasic SS. Twenty-three primary and metastatic samples from 21 patients were analysed by immunophenotyping (23/23), immunoprecipitations and Western blotting (3/23), and RT-PCR (23/23). Ten cases were biphasic and 13 monophasic in sub-type. Twelve, 10 and 1 case carried the SYT-SSX1, SYT-SSX2 and SYT-SSX4 fusion transcript, respectively. Co-presence of both c-Kit and SCF mRNA was observed in almost all cases (20/23), suggesting the occurrence of an autocrine loop. Immunophenotyping, confirmed by biochemical analyses, showed a modulation of c-Kit expression which was faint in the spindle and strong in the epithelial component, respectively. The study was complemented by c-Met/HGF receptor/ligand expression and c-Met protein analysis with results superimposable to those already reported. Since in each tumour, epithelial and spindle cell components harbour the same type of translocation t(X;18) the present findings suggest a shifting of the anti-apoptotic role from BCL2 to c-KIT gene during the transition from the uncommitted spindle to the differentiated epithelial cells.
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PMID:c-KIT and c-KIT ligand (SCF) in synovial sarcoma (SS): an mRNA expression analysis in 23 cases. 1148 73

Fluorescence in situ hybridization (FISH) is difficult to accomplish using thin-sections of paraffin-embedded lymphoid tissue because of the high cellularity and truncated cells that interfere with accurate scoring of individual nuclei. We modified and tested a new technique to isolate individual nuclei from tissue cores of paraffin-embedded tissue processed with xylene, proteinase K, citric acid, and pepsin. The efficacy of this method to study paraffin-embedded tissue was investigated in six normal lymph nodes or tonsils and 32 malignant lymphomas including five mantle cell, five follicular, five Burkitt, five extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue, five anaplastic large-cell, and seven diffuse large B-cell. Fusion of CCND1 and IgH, BCL2 and IgH, c-myc and IgH, and MALT1 and API2 were detected using probes with a dual-fusion FISH strategy. Anomalies involving ALK and BCL6 were detected using break-apart FISH probes. FISH studies were successful for each of the 38 specimens. Chromosome anomalies were detected in each malignant specimen, but not in the normal lymphoid tissue. The correct chromosome anomaly was detected in 22 of 22 specimens with genetic abnormalities that were established by other genetic techniques. This FISH technique is useful to detect chromosome anomalies with high sensitivity and specificity in paraffin-embedded tissue and may provide important diagnostic and prognostic genetic information.
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PMID:A new method to extract nuclei from paraffin-embedded tissue to study lymphomas using interphase fluorescence in situ hybridization. 1205 1

To investigate genetic alterations in primary cutaneous B-cell lymphomas (PCBCLs), we have analyzed 29 cases of PCBCL. Comparative genomic hybridization showed chromosome imbalances (CIs) in 12 cases (41%). The mean number of CIs per sample was 2.05 +/- 2.97, with gains (1.48 +/- 2.38) more frequent than losses (0.56 +/- 1.40). The common regions of gains were 18/18q (50%), 7/7p (42%), 3/3q (33%), 20 (33%), 1p (25%), 12/12q (25%), and 13/13q (25%), whereas loss of 6q was frequent (42%). Among the different subsets of PCBCLs, CI was seen in 50% of diffuse large-cell lymphomas (DLCLs), 33% of marginal zone lymphomas, and 8% of follicle center cell lymphomas and unclassified lymphomas. A similar pattern of CI was observed in these lymphomas, but loss of 6q and gains of 3/3q were present only in DLCLs. Microarray-based genomic analysis of four DLCL cases identified oncogene gains of SAS/CDK4 (12q13.3) in three cases and MYCL1 (1p34.3), MYC (8q24), FGFR2 (10q26), BCL2 (18q21.3), CSE1L (20q13), and PDGFB (22q12-13) in two cases, whereas losses of AKT1 (14q32.3), IGFR1 (15q25-26), and JUNB (19p13.2) were identified in three cases, and losses of FGR (1p36), ESR (6q25.1), ABL1 (9q34.1), TOP2A (17q21-22), ERBB2 (17q21.2), CCNE1 (19q13.1), and BCR (22q11) were each identified in two cases. In addition, real-time-polymerase chain reaction detected amplification of BCL2 in 5 of 29 cases. These findings suggest that there are complex but consistent genetic alterations associated with the pathogenesis of PCBCLs.
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PMID:Comparative genomic hybridization analysis of primary cutaneous B-cell lymphomas: identification of common genomic alterations in disease pathogenesis. 1220 78


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