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)

Human T cell leukemia/lymphoma virus type-1 (HTLV-1) is recognized as the etiological agent of adult T cell leukemia (ATL). Although HTLV-1 can immortalize human lymphocytes in culture, identification of molecular events leading to tumorigenesis after HTLV-1 infection remain elusive. SCID/bg and NOD/SCID mice have reduced natural killer (NK) cell activity and were inoculated intraperitoneally with HTLV-1 transformed cells to refine and characterize the SCID mouse as a small animal model for investigation of HTLV-1 tumorigenesis. HTLV-1 transformed cell lines originally derived by cocultivation of uninfected peripheral blood mononuclear cells (PBMC) with lethally irradiated leukemic cells from patient samples (SLB-1, MT-2 and HT-1-RV) were lymphomagenic when inoculated into NOD/SCID mice. In contrast, immortalized cell lines generated by transfection PBMC with an infectious molecular clone of HTLV-1 (ACH or ACH.p12) were not tumorigenic. The differing behaviors of HTLV-1 infected cell lines in NOD/SCID mice indicates that viral infection and immortalization of human PBMC for growth in culture is not sufficient for induction of a tumorigenic phenotype. The higher level of engraftment of HTLV-1 transformed cell lines in NOD/SCID mice suggests that this is an effective animal model to investigate molecular determinants of HTLV-1 lymphomagenesis.
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PMID:Engraftment and tumorigenesis of HTLV-1 transformed T cell lines in SCID/bg and NOD/SCID mice. 1200 4

During malignant transformation in skin, epidermal keratinocytes (KCs) frequently acquire the capacity to by-pass cellular senescence, a response that normally limits their unrestricted proliferation. Despite growing interest in the role for senescence during aging of skin and cutaneous carcinogenesis, little is known regarding regulation of three proteins encoded by the INK4a/ARF locus (p12, p14(ARF), p16) in KCs. In this study, several molecular pathways are explored using cultured KCs and KCs freshly isolated from psoriatic plaques. p16 and p14(ARF) are predominantly expressed spontaneously when foreskin-derived early-passage KCs undergo confluency-induced premature senescence. Induction of p14(ARF) on confluency occurred with low E2F-1 levels. Suspension of KCs in methylcellulose induced p12 expression. Addition of various cytokines (interferon-gamma, tumor necrosis factor-alpha) or a phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] only induced p16, but not p14(ARF). Confluent KCs up-regulated Ras activity and the downstream signaling involving ERK. Addition of MAPK inhibitor blocked cytokine and TPA-induced p16 expression. Confluency and interferon-gamma induced premature senescence and p16 expression was linked to induction of the transcription factor Egr-1. KCs derived from chronic psoriatic plaques were characterized by enhanced p16, p14(ARF), and p12 expression accompanied by elevated Egr-1 levels. These results demonstrate that multiple and highly divergent stimuli can trigger the senescent checkpoint in human KCs with differential regulation of p16, p14(ARF), and p12. Although abnormal mitogenic signaling by oncogenic Ras is generally cited as being responsible for induction of premature senescence, our findings indicate that a broader perspective is warranted, to include confluency and cytokine-/TPA-induced pathways for KCs.
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PMID:Role of INK4a/Arf locus-encoded senescent checkpoints activated in normal and psoriatic keratinocytes. 1250 99

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.
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PMID:Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome. 1266 62

The 8p11-21 region is a frequent target of alterations in breast cancer and other carcinomas. We surveyed 34 breast tumor cell lines and 9 pancreatic cancer cell lines for alterations of this region by use of multicolor fluorescence in situ hybridization (M-FISH) and BAC-specific FISH. We describe a recurrent chromosome translocation breakpoint that targets the NRG1 gene on 8p12. NRG1 encodes growth factors of the neuregulin/heregulin-1 family that are ligands for tyrosine kinase receptors of the ERBB family. Breakpoints within the NRG1 gene were found in four of the breast tumor cell lines: ZR-75-1, in a dic(8;11); HCC1937, in a t(8;10)(p12;p12.1); SUM-52, in an hsr(8)(p12); UACC-812, in a t(3;8); and in two of the pancreatic cancer cell lines: PaTu I, in a der(8)t(4;8); and SUIT-2, in a del(8)(p). Mapping by two-color FISH showed that the breaks were scattered over 1.1 Mb within the NRG1 gene. It is already known that the MDA-MB-175 breast tumor cell line has a dic(8;11), with a breakpoint in NRG1 that fuses NRG1 to the DOC4 gene on 11q13. Thus, we have found a total of seven breakpoints, in two types of cancer cell lines, that target the NRG1 gene. This suggests that the NRG1 locus is a recurring target of translocations in carcinomas. PCR analysis of reverse-transcribed cell line RNAs revealed an extensive complexity of the NRG1 transcripts but failed to detect a consistent pattern of mRNA isoforms in the cell lines with NRG1 breakpoint.
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PMID:A recurrent chromosome translocation breakpoint in breast and pancreatic cancer cell lines targets the neuregulin/NRG1 gene. 1280 Jan 45

Gene amplification is an important mechanism of oncogene activation in breast and other cancers. Characterization of amplified regions of the genome in breast cancer has led to the identification of important oncogenes including erbB-2/HER-2, C-MYC, and fibroblast growth factor receptor (FGFR) 2. Chromosome 8p11-p12 is amplified in 10-15% of human breast cancers. The putative oncogene FGFR1 localizes to this region; however, we show evidence that FGFR inhibition fails to slow growth of three breast cancer cell lines with 8p11-p12 amplification. We present a detailed analysis of this amplicon in three human breast cancer cell lines using comparative genomic hybridization, traditional Southern and Northern analysis, and chromosome 8 cDNA microarray expression profiling. This study has identified new candidate oncogenes within the 8p11-p12 region, supporting the hypothesis that genes other than FGFR1 may contribute to oncogenesis in breast cancers with proximal 8p amplification.
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PMID:Genomic and expression analysis of the 8p11-12 amplicon in human breast cancer cell lines. 1472 6

Amplification of chromosomal regions leads to an increase of DNA copy number and expression of oncogenes in human breast cancer (HBC). Amplification of the 8p11-p12 region occurs in 10-15% of primary, uncultured HBCs. In our panel of 11 breast cancer cells, three cell lines, SUM-44, SUM-52, and SUM-225, have overlapping amplicons in the 8p11-p12 region. To characterize genome structure of the amplified regions, we performed fluorescence in situ hybridization using 8p11-p12 BAC clones in the 3 cell lines. The results revealed that the 8p11-p12 amplicon has a highly complex structure and that FGFR1 is not in the common core-amplified domain in 3 breast cancer cell lines with the amplicon. These 3 cell lines provide good models for genetic and functional studies of candidate oncogenes of the 8p11-p12 region.
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PMID:Genomic organization of the 8p11-p12 amplicon in three breast cancer cell lines. 1552 3

We report two new cases with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion. Case 1 presented with polycythaemia vera (PV) and evolved over 4 years to a myeloproliferative disorder (MPD) resembling the 8p11 myeloproliferative syndrome (EMS). Case 2 presented with B-cell lymphoblastic leukaemia (B-ALL). These cases illustrate the clinical heterogeneity observed in patients with FGFR1 rearrangements and suggest that constitutively activated tyrosine kinases may be more widespread in MPDs.
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PMID:Clinical variability of patients with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion: two further cases. 1557 Feb 99

Array-comparative genomic hybridization (a-CGH) is a molecular cytogenetic technique for detection of multiple chromosomal abnormalities in genomic DNA samples. Using an a-CGH with 287 probes, we examined 14 cases of breast infiltrating ductal carcinoma (IDCA) that had previously been classified by fluorescent in situ hybridization (FISH) as either human epidermal growth factor receptor-2 positive (HER2+) or HER2- and analyzed the data by hierarchical, K-means, and principal component analyses. The aim of the study was to identify the genetic abnormalities that are present in breast IDCAs and determine if the global status of 287 cytogenetic locations could be used as a more objective method for breast IDCA classification. Concordance between FISH and a-CGH at the HER2 locus was 78.6% (11/14). In general, a-CGH detected more abnormalities in HER2+ cases. In HER 2+ cases, chromosomes 1, 2, 3, 7, 9, 17, and 20 had more regions that showed statistically significant (P < or = 0.01) changes in DNA copy number. Among all the aberrant cytogenetic locations detected, 20q13, 7p12.3 approximately p12.1, and 17q23.2 approximately q25.3, which contain among others, genes for TNFRSF6B, EGFR, and TK1 showed statistically significant gains (P < or = 0.01) in 83, 66.7, and 50% of the HER2+ IDCA cases, respectively. Chromosome location 8q24.12 approximately q24.13 was the only region that showed consistent amplification in approximately 50% of the HER2- cases. Unsupervised hierarchical and K-means cluster analyses and principal component analysis using the DNA copy number status of 287 cytogenetic locations or the 177 cytogenetic locations that showed statistically significant differences revealed a cluster consisting of mainly HER2- IDCA cases. Even though this study demonstrates the usefulness of a-CGH in the rapid identification of aberrant DNA regions in tumor samples, we conclude that an array-CGH with more than 287 probes will be needed for a more precise mapping of DNA aberrations at the global level.
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PMID:Global search for chromosomal abnormalities in infiltrating ductal carcinoma of the breast using array-comparative genomic hybridization. 1557 96

The case of a patient presenting with a myeloproliferative disorder (MPD) characterized by a t(8;22) (p12;q11) translocation was investigated. The rearrangement resulted in the production of BCR-FGFR1 and FGFR1-BCR chimeric transcripts after in-frame fusions of BCR exon 4 with FGFR1 exon 9 and FGFR1 exon 8 with BCR exon 5, respectively. The four previously reported patients with such translocation presented with an atypical chronic myeloid leukemia (CML) without Philadelphia chromosome. In addition to a myeloproliferation, the patient had a B cell proliferation. The phenotypic characterization of the lymphoid cells in the bone marrow showed a continuum of maturation from blast B cells to polyclonal lymphocytes. In the blood, B cells showed a complete polyclonal maturation. The BCR-FGFR1 gene fusion was detected by dual-color fluorescence in situ hybridization in both CD19- and CD19+ populations. In contrast to the other FGFR1-MPDs that show myeloid and T cell proliferation, we propose that this t(8;22) MPD is a myeloid and B cell disease, and potentially a novel type of hematological disease. Although the FGFR1-MPD is rare, its study provides interesting clues to the understanding of hematopoietic stem cell biology and oncogene activation.
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PMID:Dual lympho-myeloproliferative disorder in a patient with t(8;22) with BCR-FGFR1 gene fusion. 1587 Aug 60

The Grb10 gene on chromosome 7p11.2-p12 belongs to a family of adapter proteins known to interact with a number of receptor tyrosine kinases, such as EGF, ErbB2/Her2, platelet-derived growth factor (PDGF), IGF-I receptors and vascular endothelial growth factor (VEGF) receptor, KDR (kinase insert domain containing receptor). In addition to receptor tyrosine kinases, Grb10 has also been found to interact with non-receptor tyrosine kinases such as Tec and Bcr-Abl, other cellular signaling molecules such as Raf-1, and the mitogen-activated protein (MAP) kinase, MEK. We demonstrated increased expression of Grb10 mRNA in more than one half of primary cervical squamous cell cancers (12 of 15 cases) when compared to corresponding non-cancerous uterine squamous cell tissues. In addition, immunohistochemical staining demonstrated that the Grb10 protein was prominent in the cytoplasm of cancer cells, whereas it was unreactive in the surrounding normal cervical squamous cells. In addition, its interruption by siRNA exhibited marked cell growth inhibition. These data indicate that amplification and increased expression of the Grb10 gene may play a role in the development of a portion of human cervical squamous cell cancer.
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PMID:Up-regulation of growth factor receptor-bound protein 10 in cervical squamous cell carcinoma. 1587 Sep 23


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