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1.
Biol J Linn Soc Lond ; 133(3): 817-834, 2021 Jul.
Article in English | MEDLINE | ID: mdl-34220190

ABSTRACT

The Northern Rocky Mountain ecosystem supports rich biological diversity with many endemic and rare species. Extant endemics display two biogeographic patterns: widespread species with fragmented populations, and narrow-range endemics. These distributions are shown by the congeneric snails Anguispira kochi occidentalis and Anguispira nimapuna. These two taxa are disjunct from the remaining species of the genus, which achieves its greatest diversity in eastern North America. Given the disjunct nature of A. k. occidentalis and A. nimapuna, we here present a mtDNA phylogeny of the genus that includes both eastern and western species to assess the phylogenetic position of A. k. occidentalis and A. nimapuna. We then reconstruct the demographic history of A. k. occidentalis and A. nimapuna by analysing current patterns of genetic variation and interpreting the results considering the historical biogeography of the region. Both A. k. occidentalis and A. nimapuna represent unique taxa that are genetically and geographically distinct from their congeners. The current distribution and genetic structure of A. k. occidentalis has been shaped by both historical isolation in refugia and more recent northward shifts, whereas A. nimapuna is represented by two populations with shallow divergence in an area of long-term habitat stability.

2.
J Hered ; 111(1): 92-102, 2020 02 05.
Article in English | MEDLINE | ID: mdl-31841140

ABSTRACT

Newly arrived species on young or remote islands are likely to encounter less predation and competition than source populations on continental landmasses. The associated ecological release might facilitate divergence and speciation as colonizing lineages fill previously unoccupied niche space. Characterizing the sequence and timing of colonization on islands represents the first step in determining the relative contributions of geographical isolation and ecological factors in lineage diversification. Herein, we use genome-scale data to estimate timing of colonization in Naesiotus snails to the Galápagos islands from mainland South America. We test inter-island patterns of colonization and within-island radiations to understand their contribution to community assembly. Partly contradicting previously published topologies, phylogenetic reconstructions suggest that most Naesiotus species form island-specific clades, with within-island speciation dominating cladogenesis. Galápagos Naesiotus also adhere to the island progression rule, with colonization proceeding from old to young islands and within-island diversification occurring earlier on older islands. Our work provides a framework for evaluating the contribution of colonization and in situ speciation to the diversity of other Galápagos lineages.


Subject(s)
Genetic Speciation , Snails/genetics , Animal Distribution , Animals , Biodiversity , Chronology as Topic , Datasets as Topic , Ecosystem , Ecuador , Phylogeny , Phylogeography , Sequence Analysis, DNA , Snails/classification
3.
Nucleic Acid Ther ; 23(5): 311-21, 2013 Oct.
Article in English | MEDLINE | ID: mdl-23971906

ABSTRACT

Prostate cancer represents approximately 10 percent of all cancer cases in men and accounts for more than a quarter of all cancer types. Advances in understanding the molecular mechanisms of prostate cancer progression, however, have not translated well to the clinic. Patients with metastatic and hormone-refractory disease have only palliative options for treatment, as chemotherapy seldom produces durable or complete responses, highlighting the need for novel therapeutic approaches. T-oligo, a single-stranded deoxyribonucleic acid with partial sequence homology to human telomeric DNA, has elicited cytostatic and/or cytotoxic effects in multiple cancer cell types. In contrast, normal primary cells of varying tissue types are resistant to cytotoxic actions of T-oligo, underscoring its potential utility as a novel targeted cancer therapeutic. Mechanistically, T-oligo is hypothesized to interfere with normal telomeric structure and form G-quadruplex structures, thereby inducing genomic stress in addition to aberrant upregulation of DNA damageresponse pathways. Here, we present data demonstrating the enhanced effectiveness of a deoxyguanosine-enriched sequence of T-oligo, termed (GGTT)4, which elicits robust cytotoxic effects in prostate cancer cells at lower concentrations than the most recent T-oligo sequence (5'-pGGT TAG GTG TAG GTT T 3') described to date and used for comparison in this study, while exerting no cytotoxic actions on nontransformed human prostate epithelial cells. Additionally, we provide evidence supporting the T-oligo induced activation of cJun N-terminal kinase (JNK) signaling in prostate cancer cells consistent with G-quadruplex formation, thereby significantly advancing the understanding of the T-oligo mechanism of action.


Subject(s)
Cytotoxins/toxicity , Deoxyguanosine/chemistry , Gene Expression Regulation, Neoplastic/drug effects , JNK Mitogen-Activated Protein Kinases/genetics , Oligonucleotides/toxicity , Prostate/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , DNA Damage , DNA, Single-Stranded , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , G-Quadruplexes , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Organ Specificity , Prostate/metabolism , Prostate/pathology , Signal Transduction , Telomere/chemistry
4.
J Cell Physiol ; 227(6): 2586-94, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21898405

ABSTRACT

DNA oligonucleotides with sequence homology to human telomeric DNA (T-oligo) induce cell cycle arrest, followed by apoptosis, senescence, or autophagy in a human cancer cell type-specific manner. T-oligo has potential as a new therapeutic strategy in oncology because of its ability to target certain types of tumor cells while sparing normal ones. In the present study, we demonstrate the T-oligo-induced S-phase cell cycle arrest in four pancreatic cancer cell lines. To further contribute to the mechanistic understanding of T-oligo, we also identify cyclin dependent kinase 2 (cdk2) as a functional mediator in the T-oligo-induced cell cycle arrest of pancreatic cancer cells. Ectopic expression of a constitutively active cdk2 mutant abrogates T-oligo-induced cell cycle arrest in these tumor cells while knockdown of cdk2 expression alone recapitulates the T-oligo effect. Finally, we demonstrate the dispensability of T-oligo-induced ATM/ATR-mediated DNA damage response-signaling pathways, which have long been considered functional in the T-oligo signaling mechanism.


Subject(s)
Oligonucleotides/metabolism , Pancreatic Neoplasms/genetics , S Phase Cell Cycle Checkpoints/genetics , Telomere/genetics , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cyclin-Dependent Kinase 2/genetics , Cyclin-Dependent Kinase 2/metabolism , DNA Damage/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Humans , Mutation , Pancreatic Neoplasms/enzymology , Pancreatic Neoplasms/pathology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/metabolism , RNA Interference , Signal Transduction/genetics , Time Factors , Transfection , Tumor Suppressor Protein p53/deficiency , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism
5.
Int J Cancer ; 124(2): 473-82, 2009 Jan 15.
Article in English | MEDLINE | ID: mdl-19003960

ABSTRACT

Human B- or T-cell lymphoma lines and primary murine lymphomas were treated with DNA oligonucleotides homologous to the telomere (TTAGGG repeat; "T-oligo"), either alone or in combination with standard, widely-used anticancer chemotherapeutic agents. T-oligo induces cell cycle arrest and apoptosis in cultured human or murine B or T-lymphoma cell lines and primary tumor cells, but exerts no detectable toxicity on normal human or murine primary lymphocytes. Exposure to T-oligo is hypothesized to mimic exposure of the 3' telomere repeat sequence, activating the ataxia telangiectasia mutated kinase, which phosphorylates downstream effectors such as p53, but effects are not dependent solely on functional p53. T-oligo causes early S-phase arrest and cooperates well with G(2)- or M-phase-specific anticancer agents; when combined at 1/10th of the conventional dose, vincristine and T-oligo produce greater-than-additive killing of human or murine lymphoma cells (78% of cells undergoing apoptosis after 6 hr vs. 5% of control cells). In mice, 1/10th of the conventional dose of a standard combination of cyclophosphamide, adriamycin, vincristine and prednisone is twice as effective when used in combination with low dose T-oligo. Thus, T-oligo sensitizes tumors to traditional anticancer agents and represents a potentially important new addition to the therapeutic arsenal for aggressive lymphomas.


Subject(s)
Apoptosis , Lymphocytes/metabolism , Lymphoma/metabolism , Oligonucleotides/chemistry , Telomere/ultrastructure , Animals , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Caspase 3/metabolism , Cell Line, Tumor , Female , Humans , Lymphocytes/pathology , Lymphoma/pathology , Maximum Tolerated Dose , Mice , Phosphorylation
6.
Anticancer Drugs ; 19(4): 329-38, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18454043

ABSTRACT

Telomeres, the specialized structures that comprise the ends of chromosomes, form a closed structure, or t-loop, that is important in preventing genomic instability. Forced modulation of this structure, via overexpression of a dominant-negative form of telomere repeat binding factor 2, a protein critical for maintaining t-loop structure, for example, can result in the activation of DNA-damage responses, and ultimately cellular senescence or apoptosis. This response is also seen in normal somatic cells, where telomeres steadily decrease in length as cellular proliferation occurs owing to inefficient replication of terminal telomeric DNA. When telomere length becomes critically short, t-loop structure is compromised, and the cell undergoes senescence. Telomerase, the enzyme responsible for telomere length maintenance, is overexpressed in a majority of cancers. Its lack of expression in most normal somatic cells makes it an attractive target in designing cancer therapeutics. Compounds currently under development that seek to inhibit hTERT, the reverse transcriptase component of telomerase, include nucleoside analogs and the small molecule BIBR1532. Compounds inhibiting the RNA component of telomerase, hTERC, include peptide nucleic acids, 2-5A antisense oligonucleotides, and N3'-P5' thio-phosphoramidates. Recently, an oligonucleotide sharing sequence homology with terminal telomeric DNA, termed 'T-oligo', has shown cytotoxic effects in multiple cancers in culture and animal models. Independent of telomerase function, T-oligo is thought to mimic the DNA-damage response a cell normally experiences when the telomere t-loop structure becomes dysfunctional. In this review, the molecular mechanisms attributed to telomerase inhibitors and T-oligo, as well as their potential as cancer therapeutics, are discussed.


Subject(s)
Antineoplastic Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Neoplasms/drug therapy , Oligonucleotides/therapeutic use , Telomerase/antagonists & inhibitors , Acridines/pharmacology , Acridines/therapeutic use , Aminobenzoates/pharmacology , Aminobenzoates/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Humans , Naphthalenes/pharmacology , Naphthalenes/therapeutic use , Neoplasms/enzymology , Oligonucleotides/pharmacology , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , Telomere/genetics , Telomere/physiology , Tumor Cells, Cultured
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