Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer.


:To assess telomerase as a cancer therapeutic target and determine adaptive mechanisms to telomerase inhibition, we modeled telomerase reactivation and subsequent extinction in T cell lymphomas arising in Atm(-/-) mice engineered with an inducible telomerase reverse transcriptase allele. Telomerase reactivation in the setting of telomere dysfunction enabled full malignant progression with alleviation of telomere dysfunction-induced checkpoints. These cancers possessed copy number alterations targeting key loci in human T cell lymphomagenesis. Upon telomerase extinction, tumor growth eventually slowed with reinstatement of telomere dysfunction-induced checkpoints, yet growth subsequently resumed as tumors acquired alternative lengthening of telomeres (ALT) and aberrant transcriptional networks centering on mitochondrial biology and oxidative defense. ALT+ tumors acquired amplification/overexpression of PGC-1β, a master regulator of mitochondrial biogenesis and function, and they showed marked sensitivity to PGC-1β or SOD2 knockdown. Genetic modeling of telomerase extinction reveals vulnerabilities that motivate coincidental inhibition of mitochondrial maintenance and oxidative defense mechanisms to enhance antitelomerase cancer therapy.






Hu J,Hwang SS,Liesa M,Gan B,Sahin E,Jaskelioff M,Ding Z,Ying H,Boutin AT,Zhang H,Johnson S,Ivanova E,Kost-Alimova M,Protopopov A,Wang YA,Shirihai OS,Chin L,DePinho RA




Has Abstract


2012-02-17 00:00:00
















  • MazF, an mRNA interferase, mediates programmed cell death during multicellular Myxococcus development.

    abstract::In prokaryotes, the toxin-antitoxin systems are thought to play important roles in growth regulation under stress conditions. In the E. coli MazE-MazF system, MazF toxin functions as an mRNA interferase cleaving mRNAs at ACA sequences to inhibit protein synthesis leading to cell growth arrest. Myxococcus xanthus is a ...


    pub_type: 杂志文章


    authors: Nariya H,Inouye M

    更新日期:2008-01-11 00:00:00

  • Swaying is a mutant allele of the proto-oncogene Wnt-1.

    abstract::Mice homozygous for the recessive mutation swaying (sw) are characterized by ataxia and hypertonia, attributed to the malformation of anterior regions of the cerebellum. We show that sw is a deletion of a single base pair from the proto-oncogene Wnt-1. The deletion is predicted to cause premature termination of transl...


    pub_type: 杂志文章


    authors: Thomas KR,Musci TS,Neumann PE,Capecchi MR

    更新日期:1991-11-29 00:00:00

  • Sequence from early region of polyoma virus DNA containing viral replication origin and encoding small, middle and (part of) large T antigens.

    abstract::The sequence of about one third of the polyoma virus genome is presented. This sequence covers the origin of replication of two large plaque strains (A2 and A3) of polyoma virus. The two strains differ by 11 bp in the origin region. A model for replication is suggested. The sequence probably also covers the entire cod...


    pub_type: 杂志文章


    authors: Soeda E,Arrand JR,Smolar N,Griffin BE

    更新日期:1979-06-01 00:00:00

  • Friction Mediates Scission of Tubular Membranes Scaffolded by BAR Proteins.

    abstract::Membrane scission is essential for intracellular trafficking. While BAR domain proteins such as endophilin have been reported in dynamin-independent scission of tubular membrane necks, the cutting mechanism has yet to be deciphered. Here, we combine a theoretical model, in vitro, and in vivo experiments revealing how ...


    pub_type: 杂志文章


    authors: Simunovic M,Manneville JB,Renard HF,Evergren E,Raghunathan K,Bhatia D,Kenworthy AK,Voth GA,Prost J,McMahon HT,Johannes L,Bassereau P,Callan-Jones A

    更新日期:2017-06-29 00:00:00

  • The Ancient Gamete Fusogen HAP2 Is a Eukaryotic Class II Fusion Protein.

    abstract::Sexual reproduction is almost universal in eukaryotic life and involves the fusion of male and female haploid gametes into a diploid cell. The sperm-restricted single-pass transmembrane protein HAP2-GCS1 has been postulated to function in membrane merger. Its presence in the major eukaryotic taxa-animals, plants, and ...


    pub_type: 杂志文章


    authors: Fédry J,Liu Y,Péhau-Arnaudet G,Pei J,Li W,Tortorici MA,Traincard F,Meola A,Bricogne G,Grishin NV,Snell WJ,Rey FA,Krey T

    更新日期:2017-02-23 00:00:00

  • Auxin distribution and plant pattern formation: how many angels can dance on the point of PIN?

    abstract::The plant hormone auxin is central in patterning diverse plant tissues. The direction of auxin flow and the distribution of auxin within tissues are regulated by auxin efflux transporters that are polarly localized in cells. Feedback regulation between auxin and its transporters establishes homeostatic patterns of aux...


    pub_type: 杂志文章,评审


    authors: Leyser O

    更新日期:2005-06-17 00:00:00

  • double-time is a novel Drosophila clock gene that regulates PERIOD protein accumulation.

    abstract::We have isolated three alleles of a novel Drosophila clock gene, double-time (dbt). Short- (dbtS) and long-period (dbtL) mutants alter both behavioral rhythmicity and molecular oscillations from previously identified clock genes, period and timeless. A third allele, dbtP, causes pupal lethality and eliminates circadia...


    pub_type: 杂志文章


    authors: Price JL,Blau J,Rothenfluh A,Abodeely M,Kloss B,Young MW

    更新日期:1998-07-10 00:00:00

  • Abelson leukemia virus induces lymphoid and erythroid colonies in infected fetal cell cultures.

    abstract::An examination of Abelson murine leukemia virus (A-MuL V)-hematopoietic cell interaction in cultures of fetal tissues reveals that A-MuLV can stimulate the formation of two different types of colonies. One type of colony is white and composed of A-MuLV-transformed lymphoid cells that can develop into established cell ...


    pub_type: 杂志文章


    authors: Waneck GL,Rosenberg N

    更新日期:1981-10-01 00:00:00

  • Protein degradation in E. coli: the lon mutation and bacteriophage lambda N and cII protein stability.

    abstract::The Ion gene of E. coli controls the stability of two bacteriophage lambda proteins. The functional half-life of the phage N gene product, measured by complementation, is increased about 5-fold in Ion mutant strains, from 2 min to 10 min. The chemical half-life of N protein, determined by its disappearance on polyacry...


    pub_type: 杂志文章


    authors: Gottesman S,Gottesman M,Shaw JE,Pearson ML

    更新日期:1981-04-01 00:00:00

  • Top to Tail: Anterior-Posterior Patterning Precedes Regional Nervous System Identity.

    abstract::In this issue, Metzis et al., demonstrate that in the development of the central nervous system, patterning along the anterior-posterior axis precedes acquisition of neural identity. This contrasts with the prevailing view that neural identity comes first, providing a new window on the origins of the brain and spinal ...


    pub_type: 评论,杂志文章


    authors: Simon CS,Hadjantonakis AK

    更新日期:2018-11-01 00:00:00

  • A deeper look into translation initiation.

    abstract::Eukaryotic translation initiation requires coordinated assembly of a remarkable array of initiation factors onto the small ribosomal subunit to select an appropriate mRNA start codon. Studies from Erzberger et al. and Hussain et al. bring new insights into this mechanism by looking at early and late initiation interme...


    pub_type: 评论,杂志文章


    authors: Korostelev AA

    更新日期:2014-10-23 00:00:00

  • Alzheimer mechanisms and therapeutic strategies.

    abstract::There are still no effective treatments to prevent, halt, or reverse Alzheimer's disease, but research advances over the past three decades could change this gloomy picture. Genetic studies demonstrate that the disease has multiple causes. Interdisciplinary approaches combining biochemistry, molecular and cell biology...


    pub_type: 杂志文章,评审


    authors: Huang Y,Mucke L

    更新日期:2012-03-16 00:00:00

  • Identification of mouse sperm SED1, a bimotif EGF repeat and discoidin-domain protein involved in sperm-egg binding.

    abstract::We report the identification of SED1, a protein required for mouse sperm binding to the egg zona pellucida. SED1 is homologous to a small group of secreted cell-matrix adhesive proteins that contain Notch-like EGF repeats and discoidin/F5/8 type C domains. SED1 is expressed in spermatogenic cells and is secreted by th...


    pub_type: 杂志文章


    authors: Ensslin MA,Shur BD

    更新日期:2003-08-22 00:00:00

  • Modeling recent human evolution in mice by expression of a selected EDAR variant.

    abstract::An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in centra...


    pub_type: 杂志文章


    authors: Kamberov YG,Wang S,Tan J,Gerbault P,Wark A,Tan L,Yang Y,Li S,Tang K,Chen H,Powell A,Itan Y,Fuller D,Lohmueller J,Mao J,Schachar A,Paymer M,Hostetter E,Byrne E,Burnett M,McMahon AP,Thomas MG,Lieberman DE,Jin

    更新日期:2013-02-14 00:00:00

  • Sub-nucleosomal Genome Structure Reveals Distinct Nucleosome Folding Motifs.

    abstract::Elucidating the global and local rules that govern genome-wide, hierarchical chromatin architecture remains a critical challenge. Current high-throughput chromosome conformation capture (Hi-C) technologies have identified large-scale chromatin structural motifs, such as topologically associating domains and looping. H...


    pub_type: 杂志文章


    authors: Ohno M,Ando T,Priest DG,Kumar V,Yoshida Y,Taniguchi Y

    更新日期:2019-01-24 00:00:00

  • PSGL-1 recognition of P-selectin is controlled by a tyrosine sulfation consensus at the PSGL-1 amino terminus.

    abstract::P-selectin binding to neutrophils requires a specific protein, P-selectin glycoprotein ligand 1 (PSGL-1), as well as sialyl-Lewis X (sLex) glycan determinants. We have found that a short segment near the amino terminus of PSGL-1 that contains a tyrosine sulfation consensus is essential for P-selectin adhesion and that...


    pub_type: 杂志文章


    authors: Pouyani T,Seed B

    更新日期:1995-10-20 00:00:00

  • The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats.

    abstract::I have identified an activity in crude HeLa cell extracts that satisfies the requirements for a human telomere terminal transferase or telomerase. It catalyzes the addition of a 6 nucleotide repeating pattern to oligonucleotide primers containing human or nonhuman telomeric repeat sequences. Direct sequence analyses o...


    pub_type: 杂志文章


    authors: Morin GB

    更新日期:1989-11-03 00:00:00

  • Enhancer activation requires trans-recruitment of a mega transcription factor complex.

    abstract::Enhancers provide critical information directing cell-type-specific transcriptional programs, regulated by binding of signal-dependent transcription factors and their associated cofactors. Here, we report that the most strongly activated estrogen (E2)-responsive enhancers are characterized by trans-recruitment and in ...


    pub_type: 杂志文章


    authors: Liu Z,Merkurjev D,Yang F,Li W,Oh S,Friedman MJ,Song X,Zhang F,Ma Q,Ohgi KA,Krones A,Rosenfeld MG

    更新日期:2014-10-09 00:00:00

  • A Conserved Circular Network of Coregulated Lipids Modulates Innate Immune Responses.

    abstract::Lipid composition affects the biophysical properties of membranes that provide a platform for receptor-mediated cellular signaling. To study the regulatory role of membrane lipid composition, we combined genetic perturbations of sphingolipid metabolism with the quantification of diverse steps in Toll-like receptor (TL...


    pub_type: 杂志文章


    authors: Köberlin MS,Snijder B,Heinz LX,Baumann CL,Fauster A,Vladimer GI,Gavin AC,Superti-Furga G

    更新日期:2015-07-02 00:00:00

  • Messenger RNA for the Ad2 DNA binding protein: DNA sequences encoding the first leader and heterogenity at the mRNA 5' end.

    abstract::During the early stage of Ad2 infection of human cells, RNA is transcribed from five separate transcription units. Early region II encodes the mRNA for a 72K single-stranded DNA binding protein (DBP) which functions in DNA replication. This report describes the structure of the first leader of the DBP mRNA and the fla...


    pub_type: 杂志文章


    authors: Baker CC,Herisse J,Courtois G,Galibert F,Ziff E

    更新日期:1979-10-01 00:00:00

  • Generation of Blastocyst-like Structures from Mouse Embryonic and Adult Cell Cultures.

    abstract::A single mouse blastomere from an embryo until the 8-cell stage can generate an entire blastocyst. Whether laboratory-cultured cells retain a similar generative capacity remains unknown. Starting from a single stem cell type, extended pluripotent stem (EPS) cells, we established a 3D differentiation system that enable...


    pub_type: 杂志文章


    authors: Li R,Zhong C,Yu Y,Liu H,Sakurai M,Yu L,Min Z,Shi L,Wei Y,Takahashi Y,Liao HK,Qiao J,Deng H,Nuñez-Delicado E,Rodriguez Esteban C,Wu J,Izpisua Belmonte JC

    更新日期:2019-10-17 00:00:00

  • A cellular gene encodes scrapie PrP 27-30 protein.

    abstract::A clone encoding PrP 27-30, the major protein in purified preparations of scrapie agent, was selected from a scrapie-infected hamster brain cDNA library by oligonucleotide probes corresponding to the N terminus of the protein. Southern blotting with PrP cDNA revealed a single gene with the same restriction patterns in...


    pub_type: 杂志文章


    authors: Oesch B,Westaway D,Wälchli M,McKinley MP,Kent SB,Aebersold R,Barry RA,Tempst P,Teplow DB,Hood LE

    更新日期:1985-04-01 00:00:00

  • A Single Transcription Factor Drives Toxoplasma gondii Differentiation.

    abstract::Microbes that cause persistent infections (e.g., herpes viruses) do so by switching from fast-growing lytic states to slow-growing latent states. Waldman et al. have identified a single transcription factor that governs the switch between the lytic and latent forms of Toxoplasma gondii, a parasite that causes a persis...


    pub_type: 评论,杂志文章


    authors: Kochanowsky JA,Koshy AA

    更新日期:2020-01-23 00:00:00

  • Identification of F-actin as the dynamic hub in a microbial-induced GTPase polarity circuit.

    abstract::Polarity in mammalian cells emerges from the assembly of signaling molecules into extensive biochemical interaction networks. Despite their complexity, bacterial pathogens have evolved parsimonious mechanisms to hijack these systems. Here, we develop a tractable experimental and theoretical model to uncover fundamenta...


    pub_type: 杂志文章


    authors: Orchard RC,Kittisopikul M,Altschuler SJ,Wu LF,Süel GM,Alto NM

    更新日期:2012-02-17 00:00:00

  • Suppressor mutations that restore export of a protein with a defective signal sequence.

    abstract::A selection procedure is described that should allow the genetic identification of cellular components involved in the process of protein localization in Escherichia coli. This procedure makes use of mutations that alter the signal sequence of the lambda receptor protein (product of the lamB gene), and prevent export ...


    pub_type: 杂志文章


    authors: Emr SD,Hanley-Way S,Silhavy TJ

    更新日期:1981-01-01 00:00:00

  • The excision of intervening sequences from Salmonella 23S ribosomal RNA.

    abstract::Novel, approximately 90 bp intervening sequences (IVs) were discovered within the 23S rRNA genes of S. typhimurium and S. arizonae. These non-rRNA sequences are transcribed and then excised during rRNA maturation. The rRNA fragments that result from the excision of the extra sequences are not religated. This results i...


    pub_type: 杂志文章


    authors: Burgin AB,Parodos K,Lane DJ,Pace NR

    更新日期:1990-02-09 00:00:00

  • Phosphoinositides in mitogenesis: neomycin inhibits thrombin-stimulated phosphoinositide turnover and initiation of cell proliferation.

    abstract::Thrombin stimulates 32Pi incorporation into phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4,5-bis-phosphate (PIP2), and phosphatidylinositol (PI), and initiates DNA synthesis in hamster (NIL) fibroblasts at a half-maximal concentration of 125 ng/ml. Neomycin, which binds PIP2 and PIP, inhibits both thro...


    pub_type: 杂志文章


    authors: Carney DH,Scott DL,Gordon EA,LaBelle EF

    更新日期:1985-09-01 00:00:00

  • Mechanical feedback through E-cadherin promotes direction sensing during collective cell migration.

    abstract::E-cadherin is a major homophilic cell-cell adhesion molecule that inhibits motility of individual cells on matrix. However, its contribution to migration of cells through cell-rich tissues is less clear. We developed an in vivo sensor of mechanical tension across E-cadherin molecules, which we combined with cell-type-...


    pub_type: 杂志文章


    authors: Cai D,Chen SC,Prasad M,He L,Wang X,Choesmel-Cadamuro V,Sawyer JK,Danuser G,Montell DJ

    更新日期:2014-05-22 00:00:00

  • A Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward.

    abstract::Nociceptin and its receptor are widely distributed throughout the brain in regions associated with reward behavior, yet how and when they act is unknown. Here, we dissected the role of a nociceptin peptide circuit in reward seeking. We generated a prepronociceptin (Pnoc)-Cre mouse line that revealed a unique subpopula...


    pub_type: 杂志文章


    authors: Parker KE,Pedersen CE,Gomez AM,Spangler SM,Walicki MC,Feng SY,Stewart SL,Otis JM,Al-Hasani R,McCall JG,Sakers K,Bhatti DL,Copits BA,Gereau RW,Jhou T,Kash TJ,Dougherty JD,Stuber GD,Bruchas MR

    更新日期:2019-07-25 00:00:00

  • Fertile waters for aging research.

    abstract::The quest to slow aging has come far, and what used to be the domain of science fiction writers and snake oil salesmen may soon become science fact. Innovative new approaches, such as the use of the very short-lived African killifish (Harel et al.), are bridging the translational gap and bring the promise of healthy l...


    pub_type: 评论,杂志文章


    authors: Wang AM,Promislow DEL,Kaeberlein M

    更新日期:2015-02-26 00:00:00