A-T-rich scaffold attachment regions flank the hematopoietic serine protease genes clustered on chromosome 14q11.2

We have analyzed approximately 70 kb of the chromosome 14q11.2 hematopoietic serine protease gene cluster for the presence of nuclear scaffold attachment regions (SARs). At least 12 potential attachment sites were identified. SARs are present on both sides of the CGL-1/CSP- B and CGL-2/CCP-X genes and upstream from the cathepsin G (CG) gene. We have further characterized the SARs immediately flanking the cytotoxic lymphocyte-specific CGL-1/CSP-B gene. These 5′ and 3′ SARs are highly A- T-rich, contain multiple attachment sites, and are associated with the scaffolds of nuclei derived from both lymphoid and erythroid cell lines. These SARs contain multiple consensus elements frequently associated with A-T-rich sequences, including the vertebrate topoisomerase II (topo II) consensus sequence, the A-box and T-box elements, and the yeast autonomous replicating sequence (ARS). The potential role for the nuclear scaffold in the transcriptional regulation of CGL-1/CSP-B expression is discussed.

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Molecular cloning, chromosomal location, and tissue-specific expression of the murine cathepsin G gene

Blood ◽

10.1182/blood.v81.6.1614.bloodjournal8161614 ◽

1993 ◽

Vol 81 (6) ◽

pp. 1614-1623 ◽

Cited By ~ 1

Author(s):

JW Heusel ◽

EM Scarpati ◽

NA Jenkins ◽

DJ Gilbert ◽

NG Copeland ◽

...

Keyword(s):

Serine Protease ◽

Serine Proteases ◽

Catalytic Triad ◽

Small Population ◽

Cathepsin G ◽

Protease Gene ◽

Chromosome 14 ◽

Gene Encoding ◽

Specific Expression ◽

Reading Frame

We previously have characterized a cluster of genes encoding cathepsin G (CG) and two other CG-like hematopoietic serine proteases, CGL-1 and CGL-2, on human chromosome 14. In this report, we clone and characterize a novel, related murine hematopoietic serine protease gene using human CG (hCG) cDNA as the probe. This murine gene spans approximately 2.5 kb of genomic DNA, is organized into five exons and four introns, and bears a high degree of homology to hCG at both nucleic acid (73%) and deduced amino acid (66%) levels. The predicted cDNA contains an open reading frame of 783 nucleotides that encodes a nascent protein of 261 amino acids. Processing of a putative signal (pre) peptide of 18 residues and an activation (pro) dipeptide would generate a mature enzyme of approximately 27 Kd that has an estimated pI of 12.0. Conserved residues at His44, Asp88, and Ser181 form the characteristic catalytic triad of the serine protease superfamily. The gene is tightly linked to the CTLA-1 locus on murine chromosome 14, where the serine protease genes mCCP1–4 are clustered. Expression of this gene is detected only in the bone marrow and is restricted to a small population of early myeloid cells. These findings are consistent with the identification of the gene encoding murine CG.

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Molecular cloning, chromosomal location, and tissue-specific expression of the murine cathepsin G gene

Blood ◽

10.1182/blood.v81.6.1614.1614 ◽

1993 ◽

Vol 81 (6) ◽

pp. 1614-1623 ◽

Cited By ~ 25

Author(s):

JW Heusel ◽

EM Scarpati ◽

NA Jenkins ◽

DJ Gilbert ◽

NG Copeland ◽

...

Keyword(s):

Serine Protease ◽

Serine Proteases ◽

Catalytic Triad ◽

Small Population ◽

Cathepsin G ◽

Protease Gene ◽

Chromosome 14 ◽

Gene Encoding ◽

Specific Expression ◽

Reading Frame

Abstract We previously have characterized a cluster of genes encoding cathepsin G (CG) and two other CG-like hematopoietic serine proteases, CGL-1 and CGL-2, on human chromosome 14. In this report, we clone and characterize a novel, related murine hematopoietic serine protease gene using human CG (hCG) cDNA as the probe. This murine gene spans approximately 2.5 kb of genomic DNA, is organized into five exons and four introns, and bears a high degree of homology to hCG at both nucleic acid (73%) and deduced amino acid (66%) levels. The predicted cDNA contains an open reading frame of 783 nucleotides that encodes a nascent protein of 261 amino acids. Processing of a putative signal (pre) peptide of 18 residues and an activation (pro) dipeptide would generate a mature enzyme of approximately 27 Kd that has an estimated pI of 12.0. Conserved residues at His44, Asp88, and Ser181 form the characteristic catalytic triad of the serine protease superfamily. The gene is tightly linked to the CTLA-1 locus on murine chromosome 14, where the serine protease genes mCCP1–4 are clustered. Expression of this gene is detected only in the bone marrow and is restricted to a small population of early myeloid cells. These findings are consistent with the identification of the gene encoding murine CG.

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Developmental regulation of topoisomerase II sites and DNase I-hypersensitive sites in the chicken beta-globin locus

Molecular and Cellular Biology ◽

10.1128/mcb.10.6.2774-2786.1990 ◽

1990 ◽

Vol 10 (6) ◽

pp. 2774-2786

Author(s):

M Reitman ◽

G Felsenfeld

Keyword(s):

Dna Cleavage ◽

Topoisomerase Ii ◽

Dnase I ◽

Erythroid Cell ◽

Globin Genes ◽

Beta Globin ◽

Dnase I Hypersensitive Sites ◽

Hypersensitive Sites ◽

Topo Ii ◽

Erythroid Development

We have mapped DNase I-hypersensitive sites and topoisomerase II (topo II) sites in the chicken beta-globin locus, which contains four globin genes (5'-rho-beta H-beta A-epsilon-3'). In the 65 kilobases (kb) mapped, 12 strong hypersensitive sites were found clustered within the 25-kb region from 10 kb upstream of rho to just downstream of epsilon. The strong sites were grouped into several classes based on their tissue distribution, developmental pattern, and location. (i) One site was present in all cells examined, both erythroid and nonerythroid. (ii) Three sites, located upstream of the rho-globin gene, were present at every stage of erythroid development, but were absent from nonerythroid cells. (iii) Four sites at the 5' ends of each of the four globin genes were hypersensitive only in the subset of erythroid cells that were transcribing or had recently transcribed the associated gene. (iv) Another three sites, whose pattern of hypersensitivity also correlated with expression of the associated gene, were found 3' of rho, beta H, and epsilon. (v) A site 3' of beta A and 5' of epsilon was erythroid cell specific and present at all developmental stages, presumably reflecting the activity of this enhancer throughout erythroid development. We also mapped the topo II sites in this locus, as determined by teniposide-induced DNA cleavage. All strong teniposide-induced cleavages occurred at DNase I-hypersensitive sites, while lesser amounts of cleavage were observed in transcribed regions of DNA. Most but not all of the DNase I-hypersensitive sites were topo II sites. These data are consistent with the hypothesis that, in vivo, topo II preferentially acts on nucleosome-free regions of DNA but suggest that additional topo II regulatory mechanisms must exist.

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Developmental regulation of topoisomerase II sites and DNase I-hypersensitive sites in the chicken beta-globin locus.

Molecular and Cellular Biology ◽

10.1128/mcb.10.6.2774 ◽

1990 ◽

Vol 10 (6) ◽

pp. 2774-2786 ◽

Cited By ~ 79

Author(s):

M Reitman ◽

G Felsenfeld

Keyword(s):

Dna Cleavage ◽

Topoisomerase Ii ◽

Dnase I ◽

Erythroid Cell ◽

Globin Genes ◽

Beta Globin ◽

Dnase I Hypersensitive Sites ◽

Hypersensitive Sites ◽

Topo Ii ◽

Erythroid Development

We have mapped DNase I-hypersensitive sites and topoisomerase II (topo II) sites in the chicken beta-globin locus, which contains four globin genes (5'-rho-beta H-beta A-epsilon-3'). In the 65 kilobases (kb) mapped, 12 strong hypersensitive sites were found clustered within the 25-kb region from 10 kb upstream of rho to just downstream of epsilon. The strong sites were grouped into several classes based on their tissue distribution, developmental pattern, and location. (i) One site was present in all cells examined, both erythroid and nonerythroid. (ii) Three sites, located upstream of the rho-globin gene, were present at every stage of erythroid development, but were absent from nonerythroid cells. (iii) Four sites at the 5' ends of each of the four globin genes were hypersensitive only in the subset of erythroid cells that were transcribing or had recently transcribed the associated gene. (iv) Another three sites, whose pattern of hypersensitivity also correlated with expression of the associated gene, were found 3' of rho, beta H, and epsilon. (v) A site 3' of beta A and 5' of epsilon was erythroid cell specific and present at all developmental stages, presumably reflecting the activity of this enhancer throughout erythroid development. We also mapped the topo II sites in this locus, as determined by teniposide-induced DNA cleavage. All strong teniposide-induced cleavages occurred at DNase I-hypersensitive sites, while lesser amounts of cleavage were observed in transcribed regions of DNA. Most but not all of the DNase I-hypersensitive sites were topo II sites. These data are consistent with the hypothesis that, in vivo, topo II preferentially acts on nucleosome-free regions of DNA but suggest that additional topo II regulatory mechanisms must exist.

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Anticancer Activity and Topoisomerase II Inhibition of Naphthalimides with ω-Hydroxylalkylamine Side-Chains of Different Lengths

Medicinal Chemistry ◽

10.2174/1573406414666180912105851 ◽

2019 ◽

Vol 15 (5) ◽

pp. 550-560

Author(s):

Mateusz D. Tomczyk ◽

Anna Byczek-Wyrostek ◽

Klaudia Strama ◽

Martyna Wawszków ◽

Przemysław Kasprzycki ◽

...

Keyword(s):

Anticancer Activity ◽

Cancer Cells ◽

Cell Lines ◽

Inhibitory Activity ◽

Topoisomerase Ii ◽

Significant Activity ◽

Anticancer Activities ◽

Human Colon Cancer ◽

Substitution Pattern ◽

Topo Ii

Background: The substituted 1,8-Naphthalimides (1H-benzo[de]isoquinoline-1,3(2H)- diones) are known as DNA intercalators stabilizing DNA-Topoisomerase II complexes. This interaction disrupts the cleavage-relegation equilibrium of Topo II, resulting in formation of broken strands of DNA. Objective: To investigate the influence of type of substituents and substitution positions in 1,8- naphthalimde skeleton on the inhibition of Topoisomerase II activity. Methods: The starting 1,8-naphthalimide were prepared from acenaphthene by introduction of appropriate substituents followed by condensation with ω-hydroxylakylamines of different chain length. The substituents were introduced to 1,8-naphthalimide molecule by nucleophilic substitution of leaving groups like nitro or bromo present in 4 or 4,5- positions using the ω- hydroxylalkylamines. The bioactivity of obtained compounds was examined in model cell lines. Results: Antiproliferative activity of selected compounds against HCT 116 human colon cancer cells, human non-small cell lung cells A549 and non-tumorigenic BEAS-2B human bronchial epithelium cells was examined. Several of investigated compounds exhibit a significant activity (IC50 µM to 7 µM) against model cancer cell lines. It was demonstrated that upon treatment with concentration of 200 µM, all derivatives display Topo II inhibitory activity, which may be compared with activity of Amonafide. Conclusion: The replacement of the nitro groups in the chromophore slightly reduces its anticancer activities, whereas the presence of both nitro group and ω-hydroxylalkylamine chain resulted in seriously increased anticancer activity. Obtained compounds showed Topo II inhibitory activity, moreover, influence of the substitution pattern on the ability to inhibit Topo II activity and cancer cells proliferation was observed.

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Expression and activity-dependent changes of a novel limbic-serine protease gene in the hippocampus

Journal of Neuroscience ◽

10.1523/jneurosci.15-07-05088.1995 ◽

1995 ◽

Vol 15 (7) ◽

pp. 5088-5097 ◽

Cited By ~ 151

Author(s):

ZL Chen ◽

S Yoshida ◽

K Kato ◽

Y Momota ◽

J Suzuki ◽

...

Keyword(s):

Serine Protease ◽

Protease Gene ◽

Activity Dependent ◽

Serine Protease Gene ◽

Expression And Activity

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Absence of the neutrophil serine protease cathepsin G decreases neutrophil granulocyte infiltration but does not change the severity of acute pancreatitis

Scientific Reports ◽

10.1038/s41598-019-53293-0 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Ali A. Aghdassi ◽

Daniel S. John ◽

Matthias Sendler ◽

Christian Storck ◽

Cindy van den Brandt ◽

...

Keyword(s):

Acute Pancreatitis ◽

Serine Protease ◽

Acinar Cells ◽

Neutrophil Infiltration ◽

Cathepsin G ◽

Pancreatic Acinar Cells ◽

Neutrophil Granulocyte ◽

Zymogen Activation ◽

Trypsinogen Activation ◽

Extracellular Matrix Components

AbstractAcute pancreatitis is characterized by an early intracellular protease activation and invasion of leukocytes into the pancreas. Cathepsins constitute a large group of lysosomal enzymes, that have been shown to modulate trypsinogen activation and neutrophil infiltration. Cathepsin G (CTSG) is a neutrophil serine protease of the chymotrypsin C family known to degrade extracellular matrix components and to have regulatory functions in inflammatory disorders. The aim of this study was to investigate the role of CTSG in pancreatitis. Isolated acinar cells were exposed to recombinant CTSG and supramaximal cholezystokinin stimulation. In CTSG−/− mice and corresponding controls acute experimental pancreatitis was induced by serial caerulein injections. Severity was assessed by histology, serum enzyme levels and zymogen activation. Neutrophil infiltration was quantified by chloro-acetate ersterase staining and myeloperoxidase measurement. CTSG was expessed in inflammatory cells but not in pancreatic acinar cells. CTSG had no effect on intra-acinar-cell trypsinogen activation. In CTSG−/− mice a transient decrease of neutrophil infiltration into the pancreas and lungs was found during acute pancreatitis while the disease severity remained largely unchanged. CTSG is involved in pancreatic neutrophil infiltration during pancreatitis, albeit to a lesser degree than the related neutrophil (PMN) elastase. Its absence therefore leaves pancreatitis severity essentially unaffected.

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Synthesis and anticancer evaluation of sulfur containing 9-anilinoacridines

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892816666210728122910 ◽

2021 ◽

Vol 16 ◽

Author(s):

Pranav Gupta ◽

Radhika V. Kumar ◽

Chul-Hoon Kwon ◽

Zhe-Sheng Chen

Keyword(s):

Cell Cycle ◽

Anticancer Activity ◽

Topoisomerase Ii ◽

Critical Role ◽

K562 Cells ◽

Dependent Manner ◽

Concentration Dependent Manner ◽

In Vivo Models ◽

Topo Ii ◽

Sulfur Containing

Background: DNA topoisomerases are a class of enzymes that play a critical role in fundamental biological processes of replication, transcription, recombination, repair and chromatin remodeling. Amsacrine (m-AMSA), the best-known compound of 9-anilinoacridines series was one of the first DNA-intercalating agents to be considered as a Topoisomerase II inhibitor. Objective: A series of sulfur containing 9-anilinoacridines related to amsacrine were synthesized and evaluated for their anticancer activity. Methods: Cell viability was assessed by the MTT assay. The topoisomerase II inhibitory assay was performed using the Human topoisomerase II Assay kit and flow cytometry was used to evaluate the effects on cell cycle of K562 cells. Molecular docking was performed using Schrödinger Maestro program. Results: Compound 36 was found to be the most cytotoxic of the sulfide series against SW620, K562, and MCF-7. The limited SAR suggested the importance of the methansulfonamidoacetamide side chain functionality, the lipophilicity and relative metabolic stability of 36 in contributing to the cytotoxicity. Topoisomerase II α inhibitory activity appeared to be involved in the cytotoxicity of 36 through inhibition of decatenation of kinetoplast DNA (kDNA) in a concentration dependent manner. Cell cycle analysis further showed the Topo II inhibition through accumulation of K562 cells in G2/M phase of cell cycle. Docking of 36 into the Topo II α-DNA complex suggested that it may be an allosteric inhibitor of Topo II α. Conclusion: Compound 36 exhibits anticancer activity by inhibiting topoisomerase II and it could further be evaluated in in vivo models.

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Characterization of a novel, human cytotoxic lymphocyte-specific serine protease cDNA clone (CSP-C)**

Tissue Antigens ◽

10.1111/j.1399-0039.1990.tb01787.x ◽

1990 ◽

Vol 35 (5) ◽

pp. 220-228 ◽

Cited By ~ 24

Author(s):

Jared L. Klein ◽

A. Selvakumar ◽

Joseph A. Trapani ◽

Bo Dupont

Keyword(s):

Serine Protease ◽

Cdna Clone ◽

Cytotoxic Lymphocyte

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