A time to pause

Aranda, Sanchia; Cooley, Candy

doi:10.12968/ijpn.2004.10.12.17279

Cited by 6 publications

(6 citation statements)

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“…for colonies counted from triplicate plates under each condition the nuclear c-Abl protein can contribute to the induction of apoptosis (Sawyers et al, 1994). Since Kharbanda et al (2000) have reported that c-Abl protein is directly associated with hTERT and inhibits telomerase activity, imatinib in combination with telomestatin may affect the dynamic regulation of telomeres. This observation suggests that combined use of telomerase inhibitors and imatinib or other chemotherapeutic agents may be a very useful approach to treatment of BCR-ABL-positive leukemia (Figures 3-5).…”

Section: Discussionmentioning

confidence: 99%

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

et al. 2003

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The telomerase complex is responsible for telomere maintenance and represents a promising neoplasia therapeutic target. In order to determine whether G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), might have effects on telomere dynamics and to evaluate the clinical utility, we assessed the effects of telomestatin on BCR-ABL-positive human leukemia cells. We found that treatment with telomestatin reproducibly inhibited telomerase activity in the BCR-ABLpositive leukemic cell lines OM9;22 and K562, resulting in telomere shortening. Inhibition of telomerase activity by telomestatin disrupts telomere maintenance and ultimately results in telomere dysfunction. Telomestatin completely suppressed the plating efficiency of K562 cells at 1 lm; however, telomestatin had less effects on BFU-Es and CFU-GMs colony formation from normal bone marrow CD34-positive cells. Enhanced chemosensitivity toward imatinib and chemotherapeutic agents was also observed in telomestatin-treated K562 cells. Further, the combination of telomestatin plus imatinib more effectively inhibited hematopoietic colony formation by primary human chronic myelogenous leukemia cells. Last, telomestatin induced the activation of ATM and Chk2, and subsequently increased the expression of p21 CIP1 and p27 KIP1 . These results demonstrate that telomere dysfunction induced by telomestatin activates the ATM-dependent DNA damage response. We conclude that telomerase inhibitors combined with the use of imatinib and other chemotherapeutic agents may be very useful for the treatment of human leukemia.

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Section: Discussionmentioning

confidence: 99%

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

et al. 2003

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“…Human telomeric DNA coimmunoprecipitated with hTERT antibody (Vaziri et al, 1999;Fu et al, 2000;Kharbanda et al, 2000;Wood et al, 2001) on in vivo crosslinking was performed by the standard procedure described previously (Braunstein et al, 1993;Hsu et al, 1999). Immunoprecipitated (IP) DNA was placed onto a membrane by using a dot-blotting apparatus and then hybridized with 32 P-labeled DNA probe.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

hTERT associates with human telomeres and enhances genomic stability and DNA repair

et al. 2003

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Ectopic expression of telomerase in telomerase-silent cells is sufficient to overcome senescence and to extend cellular lifespan. We show here that the catalytic subunit of human telomerase (hTERT) crosslinks telomeres. This interaction is blocked by the telomere repeat binding factor 1, but not by a dominant negative form of this protein. It is also abolished by destruction of the RNA component of telomerase as well as by mutations in the hTERT protein.Ectopic expression of hTERT leads to transcriptional alterations of a subset of genes and changes in the interaction of the telomeres with the nuclear matrix. This is associated with reduction of spontaneous chromosome damage in G 1 cells, enhancement of the kinetics of DNA repair and an increase in NTP levels. The effect on DNA repair is likely indirect as TERT does not directly affect DNA end rejoining in vitro or meiotic recombination in vivo. The observed effects of hTERT occurred rapidly before any significant lengthening of telomeres was observed. Our findings establish an intimate relationship between hTERT-telomere interactions and alteration in transcription of a subset of genes that may lead to increased genomic stability and enhanced repair of genetic damage. These novel functions of telomerase are distinct from its known effect on telomere length and have potentially important biological consequences.

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“…Moreover, inhibition of c-Abl with STI571 treatment has been shown to block araC-induced apoptosis (34). c-Abl interacts with diverse signaling molecules that are associated with the apoptotic response (17,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32); however, there has been no known interaction between c-Abl and the initiator or effector caspases. In the present studies, the functional significance of the c-Ablcaspase-9 interaction in cells is supported by the demonstration that inhibition of c-Abl with STI571 blocks autoprocessing of caspase-9 to the p35 subunit.…”

Section: C-abl Regulates Caspase-9 Autocleavagementioning

confidence: 99%

c-Abl Tyrosine Kinase Regulates Caspase-9 Autocleavage in the Apoptotic Response to DNA Damage

Raina

Pandey

Ahmad

et al. 2005

Journal of Biological Chemistry

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Activation of the initiator caspase-9 is essential for induction of apoptosis by developmental signals, oncogenic transformation, and genotoxic stress. The c-Abl tyrosine kinase is also involved in the apoptotic response to DNA damage. The present results demonstrate that c-Abl binds directly to caspase-9. We show that cAbl phosphorylates caspase-9 on Tyr-153 in vitro and in cells treated with DNA damaging agents. Moreover, inhibition of c-Abl with STI571 blocked DNA damage-induced autoprocessing of caspase-9 to the p35 subunit and activation of caspase-3. Caspase-9(Y153F) also attenuated DNA damage-induced processing of caspase-9 to p35, activation of caspase-3, and apoptosis. These findings indicate that caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress.Caspase-9 is the initiator caspase of the apoptosome, an oligomeric complex that controls the intrinsic apoptotic pathway. Formation of the apoptosome is induced by release of mitochondrial cytochrome c into the cytosol. Cytochrome c associates with Apaf-1 and thereby promotes its oligomerization and recruitment of caspase-9 (1-3). Binding to Apaf-1 increases activity of the caspase-9 protease and autocleavage of the p46 pro-caspase-9 at Asp-315 to yield p35 and p12 subunits (4 -6). Caspase-9 activation requires interaction with the Apaf-1 caspase recruitment domain, an increase in local concentrations of caspase-9, and the formation of caspase-9 dimers (7,8). Following autoprocessing in the apoptosome, caspase-9 cleaves and activates caspase-3. In turn, caspase-3 directs feedback cleavage of caspase-9 at Asp-330 to generate p37 and p10 subunits (4, 9). The caspase-9 p12, and not the p10, subunit contains four N-terminal amino acids that bind to the third baculoviral repeat of the X-linked inhibitor of apoptosis (10), which maintains caspase-9 in the inactive monomer conformation (11, 12) and functions as a tether for caspase-3 (13, 14). Other studies have demonstrated that caspase-9 activity is inhibited by Akt-mediated phosphorylation on and by extracellular signal-regulated kinase-mediated phosphorylation on . However, it is not known whether phosphorylation of caspase-9 contributes to autocleavage of this important apoptotic initiator.The c-Abl tyrosine kinase is activated in the response of cells to genotoxic stress (17). The product of the gene mutated in ataxia telangiectasia is responsible in part for c-Abl activation (18,19). Other work has demonstrated that nuclear c-Abl interacts with the DNA-dependent protein kinase (DNA-PK)-Ku complex (20,21). Phosphorylation of c-Abl by the catalytic subunit DNA-PKcs stimulates c-Abl activity (20). Activation of c-Abl by DNA damage or inhibition of DNA replication contributes to the induction of apoptosis by mechanisms in part dependent on the p53 tumor suppressor and its homolog p73 (22-26). c-Abl also contributes to DNA damage-induced activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) kinase-1, c-Jun N-terminal kinase,...

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A time to pause

Cited by 6 publications

References 0 publications

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

Activity of a novel G-quadruplex-interactive telomerase inhibitor, telomestatin (SOT-095), against human leukemia cells: involvement of ATM-dependent DNA damage response pathways

hTERT associates with human telomeres and enhances genomic stability and DNA repair

c-Abl Tyrosine Kinase Regulates Caspase-9 Autocleavage in the Apoptotic Response to DNA Damage

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