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PubMed1985

Amplified DNA of the Novikoff hepatoma nucleolus is arranged in a 7.3-kilobase tandem repeat.

We have reported previously the cloning and characterization of a nucleolar-localized 5.8-kilobase (kb) EcoRI fragment that is approximately 50-fold more highly reiterated in Novikoff hepatoma tumor cells than in normal rat liver [Parker, D. L., Busch, H., & Rothblum, L. I. (1981) Biochemistry 20, 762]. In the present study, the arrangement of these 5.8-kb EcoRI segments within the Novikoff hepatoma genome was investigated. Through the use of "indirect" restriction site mapping, partial restriction enzyme digestions, and molecular cloning, we have determined that the 5.8-kb EcoRI fragment and a 1.5-kb EcoRI fragment together constitute a 7.3-kb unit. The 7.3-kb unit is present in the hepatoma genome as a tandem repeat and constitutes the unit of the DNA that has been amplified. Studies on the arrangement of homologous sequences in the normal rat genome indicate that the amplified DNA may have been derived by a rearrangement and amplification of the nontranscribed spacer of the ribosomal DNA (rDNA) repeat.

Animals↗
PubMed1990

Isolation and characterization of human cDNA clones encoding the alpha and the alpha' subunits of casein kinase II.

Casein kinase II is a widely distributed protein serine/threonine kinase. The holoenzyme appears to be a tetramer, containing two alpha or alpha' subunits (or one of each) and two beta subunits. Complementary DNA clones encoding the subunits of casein kinase II were isolated from a human T-cell lambda gt10 library using cDNA clones isolated from Drosophila melanogaster [Saxena et al. (1987) Mol. Cell. Biol. 7, 3409-3417]. One of the human cDNA clones (hT4.1) was 2.2 kb long, including a coding region of 1176 bp preceded by 156 bp (5' untranslated region) and followed by 871 bp (3' untranslated region). The hT4.1 clone was nearly identical in size and sequence with a cDNA clone from HepG2 human hepatoma cultured cells [Meisner et al. (1989) Biochemistry 28, 4072-4076]. Another of the human T-cell cDNA clones (hT9.1) was 1.8 kb long, containing a coding region of 1053 bp preceded by 171 bp (5' untranslated region) and followed by 550 bp (3' untranslated region). Amino acid sequences deduced from these two cDNA clones were about 85% identical. Most of the difference between the two encoded polypeptides was in the carboxy-terminal region, but heterogeneity was distributed throughout the molecules. Partial amino acid sequence was determined in a mixture of alpha and alpha' subunits from bovine lung casein kinase II. The bovine sequences aligned with the 2 human cDNA-encoded polypeptides with only 2 discrepancies out of 535 amino acid positions. This confirmed that the two human T-cell cDNA clones encoded the alpha and alpha' subunits of casein kinase II. Microsequence data determined from separated preparations of bovine casein kinase II alpha subunit and alpha' subunit [Litchfield et al. (1990) J. Biol. Chem. 265, 7638-7644] confirmed that hT4.1 encoded the alpha subunit and hT9.1 encoded the alpha' subunit. These studies show that there are two distinct catalytic subunits for casein kinase II (alpha and alpha') and that the sequence of these subunits is largely conserved between the bovine and the human.

Amino Acid Sequence↗
PubMed1997

Apoptosis: molecular mechanisms and implications for cancer chemotherapy.

Apoptosis, or programmed cell death, is an orderly and genetically controlled form of cell death. In a morphological sense, it differs from necrosis in that cellular shrinkage and chromatin condensation occurs, followed by fragmentation of nuclear components within membrane-bound vesicles which are cleared by phagocytosis without damage to adjacent tissue. The molecular pathway includes an initiating phase, which starts after signalling by external triggers, such as ligation to distinct receptors or by endogenous mechanisms related to aging or to exogenous irreversible cellular or nuclear damage. The initiation phase is followed by a decision phase. During this phase transduction occurs of the apoptotic signal to nuclear and cytoplasmatic target enzymes, which includes activation of endonucleases and enzymatic alterations of the cytoskeleton. There are numerous proteins and lipid-derived moieties which modulate the apoptotic mechanism in positive or negative direction. The execution phase is started when the cell has arrived at a stage of no return. The nuclear DNA is cleaved into multiples of 180-200 basepairs, the plasma membrane integrity and the mitochondria remain initially intact, the cell splits up into apoptotic bodies, small vesicles which enclose the nuclear and cellular remnants. Finally, the clearing phase is arrived, when the apoptotic bodies are phagocytosed by adjacent cells and macrophages. It is thought that the pharmacodynamics of anticancer drugs consists of two distinct steps. The first step includes the interaction with its cellular target; which is not lethal per se. The commitment of the cell to undergo apoptosis forms the second step. The efficacy of anticancer drugs is determined by the ability to selectively sensitize tumor cells to apoptosis, which depends to a large extent from the expression of various oncogenes, such as bcl-2, p53, bax, ras, c-myc and others, and from endogenous factors. It is a challenge in pharmacological research to explore apoptosis by modulating the extrinsic and intrinsic regulators in a positive or negative direction in order to improve the efficacy of anticancer treatment.

Antineoplastic Agents↗
PubMed1990

Human breast cancer: identification of populations with a high risk of early relapse in relation to both oestrogen receptor status and c-erbB-2 overexpression.

We recently defined a new early prognostic factor, the ER+(R) status, which permits the discrimination of a group presenting a high risk of early relapse among the ER+ patients. This group was referred to as ER+(R2) in contrast to ER+(R1) which corresponded to the group of ER+ patients having a lower risk of early relapse. Taking into account the whole population including the ER- and inflammatory tumours, we have extended this view and showed that ER+(R) status is a significant predictor of disease-free survival. Determination of c-erbB-2 mRNA levels in the same series of tumours showed that high expression of c-erbB-2 mRNA is significantly correlated with ER-, inflammatory tumours and with lymph nodes involvement. Moreover, a multivariate analysis showed that c-erbB-2 mRNA overexpression was a significant predictor of early relapse (P = 0.02), as significant as ER negativity and ER+(R2). For ER+ patients a high level of c-erbB-2 mRNA constitutes a higher risk of relapse for both ER+(R1) and ER+(R2) patients. However, in the case of ER- patients, early relapses were strongly correlated with c-erbB-2 overexpression. The counterpart of this observation is that ER- patients with no overexpression of c-erbB-2 constitute a group with a relatively good prognosis.

Age Factors↗
PubMed2004

Wip-ing out cancer.

Explore the source record for details and available documents.

Breast Neoplasms↗
PubMed2025

The offonome reveals on and off states of gene expression near the detection limit of RNA-seq.

RNA-seq, widely used for gene expression profiling, provides nucleotide level genome coverage and summary gene expression values. Generally, low-expressed genes are ignored due to their unfavorable signal-to-noise ratio, however, these genes may offer crucial information, such as detecting rare cells in bulk tissues. In this study, we applied an approach that transforms the expression levels of low-expressed genes into a robust dichotomized on/off state by leveraging similarities in transcript coverage shape. Applied to three human cancer cohorts from the Cancer Genome Atlas (TCGA), chosen based on tissue morphology and anatomic site, we identified genes, the "offonome" near the detection limit, consistently or occasionally off across samples. Genes in the offonome spectrum proved useful for supervised and unsupervised applications, including characterizing oncogenic pathways, and identifying rare populations of cells in bulk tissue. Interrogating the offonome is relevant to bulk tumor analyses like TCGA, potentially expediting gene investigation in low-input situations like single cell RNA-seq.

Humans↗
PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗
PubMed2006

Optimizing the detection of hereditary non-polyposis colorectal cancer: an update.

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominant inherited disease and accounts for up to 5% of all colorectal cancer (CRC) patients. Despite the optimization of selection criteria and enhancements in molecular techniques for identifying more families with HNPCC, most cases are not recognized. Poor patient recollection of family history and inadequate family history-taking are main causative factors. We propose a new strategy for detecting HNPCC, one in which the pathologist selects patients for microsatellite instability (MSI) testing. Criteria for MSI analysis are: (1) CRC before the age of 50 years, (2) second CRC before 70 years, (3) CRC and HNPCC-associated cancer before 70 years, or (4) adenoma before 40 years. Additionally, patients with a positive MSI test and patients with a positive family history are offered referral for genetic counselling. With this strategy, at least twice the number of HNPCC patients will be identified among a population of CRC patients, and in a cost-effective, efficient and feasible way. The identification of patients with HNPCC is important because intensive surveillance can prevent death from CRC.

Adenoma↗
PubMed1992

The neurotoxin 1-methyl-4-phenylpyridinium: a selective cytostatic agent in small-cell lung cancer cell lines with neuroendocrine properties.

BACKGROUND: Small-cell lung cancer (SCLC) is a common malignancy that is usually fatal, since it metastasizes and recurs even after aggressive chemotherapy. While the cellular origin of this cancer is not well established, the cells of certain tumors exhibit neuroendocrine markers, including L-dopa decarboxylase. PURPOSE: We designed in vitro and in vivo studies to investigate whether the neuroendocrine features in classic SCLC cell lines were sufficient to make them sensitive to 1-methyl-4-phenylpyridinium (MPP+), a known neurotoxin that destroys nigrostriatal dopaminergic neurons. METHODS: Both classic SCLC cell lines (NCI-H345, NCI-H510, NCI-H187, and NCI-H146) and variant SCLC cell lines (NCI-H417, NCI-H82, NCI-H446, and NCI-H524) were exposed to MPP+ (0-512 microM) for 3 days. Inhibition of DNA synthesis was determined by [3H]thymidine incorporation assays. In a related experiment, MPP+ was removed from the classic cell line culture, and the incorporation of [3H]thymidine was determined. In the in vivo study, male athymic nude mice received subcutaneous injections of 0.5 mL tumor cells with matrigel for 10 days to enhance tumor growth, followed by MPP+ at doses of 100-400 micrograms/d given intraperitoneally for 2 days. RESULTS: All four classic SCLC cell lines showed great sensitivity to MPP+, with detachment from laminin substrates and inhibition of DNA synthesis. MPP+ interfered with [3H]thymidine incorporation and, thus, with DNA synthesis in classic SCLC cell lines at low doses (median +/- SD, 12 +/- 4 microM), whereas much higher doses (median, > 512 microM) were required to inhibit [3H]thymidine incorporation in the variant lines. Treated cells excluded trypan blue dye, showing that inhibition of DNA synthesis was not due to cytotoxicity, and the cells incorporated [3H]thymidine when MPP+ was removed from the culture medium, demonstrating that the inhibition was reversible. MPP+ inhibited the growth of the classic NCI-H187 and variant NCI-H417 cell lines implanted in nude mice. CONCLUSIONS: These results suggest that MPP+ differentially interferes with DNA synthesis in SCLC cell lines in vitro; the selective inhibitory effect on classic cell lines suggests that the neuroendocrine properties expressed by classic SCLC cells may be responsible for the differential effect. IMPLICATIONS: MPP+ exerts a cytostatic effect on these cell lines, and the differential sensitivity observed in vitro is maintained in vivo, suggesting that MPP+ or other pyridinium compounds may be of therapeutic value in SCLC.

1-Methyl-4-phenylpyridinium↗
PubMed1986

A new family of LTR-like sequences abundantly expressed in rat tumors.

We report the identification of two genome DNA fragments containing middle repetitive sequences abundantly expressed in various rat tumors but rarely in normal tissues. These fragments included homologous regions which belonged to a new family of long terminal repeat (LTR) like sequences, designated RAL elements; one displayed the solitary type and the other a provirus structure. The element was transcribed in a strand specific fashion and started from the presumptive cap site within the RAL element. The presumptive polyA addition site within the element was also utilized as evidence of the analysis of a cDNA clone containing the RAL element. This evidence suggested that transcriptional control signals within the element were functioning. Run on assay revealed that expression of the element was regulated at the transcriptional level.

Animals↗
PubMed1984

Molecular cloning of genomic DNA segments partially coding for human thymidylate synthase from the mouse cell transformant.

Mouse cells deficient in the enzyme thymidylate synthase [TS; EC 2.1.1.45] were serially transformed with human DNA to yield primary and secondary transformants which produced human TS [Ayusawa, D., Shimizu, K., Koyama, H., Takeishi, K., & Seno, T. (1983) J. Biol. Chem. 258, 48-53]. Southern blot hybridization of their genomic DNA showed that six secondary transformants examined contained in common a 5.5 kb EcoRI fragment hybridized with a human Alu sequence. From the secondary transformant genomic library constructed with phage lambda Charon 4A, two recombinant phage clones carrying Alu sequences were isolated. Restriction endonuclease mapping revealed that the insert DNAs of the two phage clones overlapped and covered a region of 19 kb in total. Within this region at least six Alu sequences were located. A 2.0 kb DNA fragment, prepared from an EcoRI fragment subcloned in plasmid pBR322 and free of Alu sequences, hybridized to a single band on RNA blots of primary and secondary transformant poly(A)+ RNA, but not to RNA of mouse wild-type and recipient cell lines. The relative amount of the presumed human TS mRNA was linearly correlated with the relative activity of human TS in various types of mouse transformant cells. These results indicate that these two phage clones contain genomic DNA sequences encoding human TS.

Animals↗
PubMed1999

Cyclin E in human cancers.

Regulators of the cell cycle such as cyclin E play an important part in neoplasia. The cyclin E protein forms a partnership with a specific protein kinase. This complex phosphorylates key substrates to initiate DNA synthesis. Cyclin-dependent kinase inhibitors (CKIs) are able to suppress the activity of cyclin E. Various substances (including proteins produced by oncogenic viruses) affect cyclin E directly or indirectly through an interaction with CKIs. These interactions are important in elucidating the mechanisms of neoplasia. They may also provide prognostic information in a wide range of common cancers. Cyclin E may even be a target for treatment of cancers in the future.

Breast Neoplasms↗