We have previously shown that PMEG diphosphate (PMEGpp) and PMEDAP diphosphate (PMEDAPpp) inhibit the enzymatic activity of human telomerase in a cell-free assay. Here, we investigated the ability of PMEG and PMEDAP to induce telomere shortening and telomerase inhibition at both transcriptional and activity level in T-lymphoblastic leukemia cells CCRF-CEM ...

In contrast to most vertebrates, invertebrate deuterostome echinoderms, such as the sea star Asterias rubens, undergo regeneration of lost body parts. The current hypothesis suggests that differentiated cells are the main source for regenerating arm in sea stars, but there is little information regarding the origin and identity of these ...

The effects of polyunsaturated fatty acids (PUFAs) obtained from the diet on colorectal cancer have been widely explored. However, controversial results have been obtained about the role played by the lipid peroxidation products of PUFAs, such as 4-hydroxy-nonenal (HNE), in the control of colon cancer growth. This aldehyde, indeed, showed ...

In the present study, we set out to investigate cytogenetic changes in the progeny of two normal human fibroblast cell strains after exposure to sparsely or densely ionizing irradiation (X-rays or 9.8MeVu(-1) carbon ions). The cells were regularly subcultured up to senescence. The transition to senescence was determined by measurement ...

Smooth muscle protein 22-alpha (SM22alpha) is known as a transformation- and shape change-sensitive actin cross-linking protein found in smooth muscle tissue and fibroblasts; however, its functional role remains uncertain. We reported previously that SM22alpha overexpression confers resistance against anti-cancer drugs or radiation via induction of metallothionein (MT) isozymes in HepG2 ...

Mitotic cells in culture show a limited replicative potential and after extended subculturing undergo a terminal growth arrest termed cellular senescence. When cells reach the senescent phenotype, this is accompanied by a significant change in the cellular phenotype and massive changes in gene expression, including the upregulation of secreted factors. ...

Telomerase, an enzyme complex that binds the chromosome ends (telomeres) and maintains telomere length and integrity, is present in germ cells, proliferative granulosa cells, germline stem cells, and neoplastic cells in the ovary, but it is absent in differentiated or aged cells. Activation of telomerase in the ovary underpins both ...

Although the phenotype of T-cell senescence has been extensively investigated, few studies have analyzed the factors that promote the generation and maintenance of naïve and memory T cells that exist throughout the lifespan of the individuals. Unlike senescent T cells, naïve and memory T cells are able to participate in ...

Abstract There are few studies of the developmental changes in B cell subsets in children. Recent data from adult populations demonstrate that alterations to B cell subsets have functional consequences and can be helpful diagnostically. Comparable studies in children have been hindered by the lack of normative data and by ...

The accumulation of senescent cells within tissues can potentially lead to biological dysfunction and manifestation of disease associated with ageing. The majority of senescent cells display a commonly altered secretome similar to a wound healing response (termed the senescence-associated secretory phenotype or SASP), which could have deleterious implications on the ...

AIMS: The aims of the study are to investigate the additive effect of exogenous short-carbon chain phospholipids, C(2)-ceramide, on an anti-cancer drug paclitaxel (PTX)-induced senescence of human non-small cell lung cancer (NSCLC) cells deficient in functional p53 and p16, and to examine whether mitogen-activated protein kinase (MAPK) plays a role ...

In this study, we identified posttranslational regulation of human telomerase reverse-transcriptase (hTERT) by the E3 ligase Hdm2. The telomerase activity generated by exogenous hTERT in U2OS cells was reduced on adriamycin treatment. The overexpressed levels of hTERT were also decreased under the same conditions. These processes were reversed by treatment ...

Background: The close correlation between telomerase activity and human telomerase reverse transcriptase (hTERT) expression has made hTERT to be considered as a selective molecular target for human cancer therapy. In this study, the ability of short-interfering RNA (siRNA) to downregulate hTERT expression and its correlation with cell growth and apoptosis ...

Abstract To achieve a more complete understanding of the molecular mechanisms underlying tumor radioresistance, we established a radioresistant cell line from the human larynx squamous cell carcinoma cell line Hep-2 after long-term radiation induction. The biological features of the resulting cell lines were characterized. cDNA microarray technology was used to ...

The assembly of a protective cap onto the telomeres of eukaryotic chromosomes suppresses genomic instability through inhibition of DNA repair activities that normally process accidental DNA breaks. We show here that the essential Cdc13-Stn1-Ten1 complex is entirely dispensable for telomere protection in non-dividing cells. However, Yku and Rap1 become crucially ...

Aberrant oncogenic signals are typically counteracted by anti-proliferative mechanisms governed principally by the p53 and Rb tumour-suppressor proteins. Apoptosis is firmly established as a potent anti-proliferative mechanism to prevent tumour growth but it is only in recent years that oncogene-induced senescence has achieved similar recognition. Senescence is defined as an ...

The intranuclear trafficking of human telomerase involves a dynamic interplay between multiple nuclear sites, most notably Cajal bodies and telomeres. Cajal bodies are proposed to serve as sites of telomerase maturation, storage, and assembly, as well as to function in the cell cycle-regulated delivery of telomerase to telomeres in human ...

Increased cell mass is one of the characteristics of senescent cells, but this event has not been clearly defined. When subcellular organellar mass was estimated with organelle-specific fluorescence dyes, we observed that most membranous organelles progressively increase in mass during cell senescence. This increase was accompanied by an increase in ...

Human telomerase reverse transcriptase (hTERT) is the catalytic component of telomerase that facilitates tumor cell invasion and proliferation. Telomerase and hTERT are remarkably upregulated in majority of cancers including glioblastoma. Interferon-gamma (IFN-gamma) modulates several cellular activities including cell cycle and multiplication through transcriptional regulation. The present investigation was designed to ...

Lysosomes are a cell organelle type processing antimicrobial activity. Here, we investigate the lysosomal activity in a primary cell line, bovine aortic endothelial cells (BAECs), during cellular aging, based on the antimicrobial activity of lysosomes isolated from BAECs at cell passages 4, 6, 8, and 10. Cytochemical analysis of lysosomes ...

BACKGROUND AND PURPOSE: Telomere length must be maintained throughout cancer cell progression and proliferation. In most tumours, telomerase activity maintains telomere length. Therefore, telomerase is a target for cancer treatments. However, some cancer cells maintain telomere length through an alternative mechanism termed 'alternative lengthening of telomeres'. To determine how telomerase ...

Telomeres are essential for chromosome stability and the regulation of the replicative life-span of somatic cells. Many studies showed that exogenous telomeric repeats could activate p53 protein. It is not known how cell dysfunction is induced by telomeric plasmids. A covalent closed circular (ccc) double-stranded plasmid containing (TTAGGG)(96) repeats (pRST5) ...

Preventing the formation of dysfunctional telomeres is essential for genomic stability. In most organisms, the ribo-nucleoprotein reverse transcriptase telomerase is responsible for telomere GT-strand elongation. However, in telomerase-negative cells, low-frequency recombination mechanisms can avert lethality by elongating critically short telomeres. This study focuses on the involvement of the budding yeast ...

We previously reported that the telomere-targeting drug telomestatin induces apoptosis accompanied by G-tail reduction and dissociation of binding protein TRF2 from telomeres in cancer cell lines but not normal or human telomerase reverse transcriptase (hTERT)-immortalized cells. Because telomere-targeting drugs induce growth arrest in normal cells at higher doses, their development ...

Telomerase-negative immortalized cells maintain their telomeres through a telomerase-independent pathway termed alternative lengthening of telomeres (ALT). The mechanism of ALT is based on homologous recombination (HR). A hallmark of ALT cells is presence of a nuclear structure termed ALT-associated promyelocytic leukemia body (APB). Here, we demonstrated that hRAD21, an important ...

In this issue of Molecular Cell, Faure et al. (2010) establish a critical role for the Mre11 complex in the recruitment of telomerase to leading- but not lagging-strand telomeres of budding yeast.

ABSTRACT Cellular senescence limits the replicative capacity of normal cells and acts as an intrinsic barrier that protects against the development of cancer. Telomere shortening-induced replicative senescence is dependent on the ATM-p53-p21 pathway but additional genes likely contribute to senescence. Here, we show that the p53-responsive gene BTG2 plays an ...

Ovarian surface epithelium is under constant physiological pressure to maintain its integrity. Environmental toxic exposure can contribute to degenerative pathologies including ovarian cancer. Based on our current understanding, we aimed at listing mechanistic insights that contribute to ovarian carcinogenesis after exposure to methyl isocyanate, an ubiquitous environmental pollutant. Ovarian epithelial ...

Telomeres are the complex end structures that confer functional integrity and positional stability to human chromosomes. Telomere research has long been dominated by length measurements and biochemical analyses. Recently, interest has shifted towards the role of their three-dimensional organization and dynamics within the nuclear volume. In the mammalian interphase nucleus, ...

Immortal bovine mammary epithelial cell lines are useful for providing an efficient indicator for transgene expression and for the technological improvement of genetic modification. The preparation of hTERT (human telomerase reverse transcriptase)-mediated immortalized MECs (mammary epithelial cells) requires a down-regulation of p16(INK4a). Here, we report the establishment of two immortal ...

Adriamycin, an anthracycline antibiotic, has been used for the treatment of various types of tumours. Adriamycin induces at least two distinct types of growth repression, such as senescence and apoptosis, in a concentration-dependent manner. Cellular senescence is a condition in which cells are unable to proliferate further, and senescent cells ...

PURPOSE: To investigate the alterations in microRNA (miRNA) expression during replicative senescence (RS) in human trabecular meshwork (HTM) cells. METHODS: Two HTM cell lines were serially passaged until they reached RS. Changes in expression of 30 miRNAs were assessed by real-time quantitative (q)-PCR. The effects of miR-146a on gene expression ...

Chromosomal and genomic instability due to telomere dysfunction is known to play an important role in carcinogenesis. To study telomere dysfunction in the surrounding background epithelium of squamous cell carcinoma in situ (CIS) of the oesophagus, we measured telomere lengths of basal and parabasal cells of epithelia with and without ...

This study examined whether c-myb acts as a survival molecule in aged cells. A previous in vitro ageing model suggested that aged cells have a higher cell capacity for survival after exposure to oxidative stress, which involves blockage of the translocation of Hsp60 from the mitochondria to the cytoplasm followed ...

Transient induction of p53 can cause reversible quiescence and irreversible senescence. Using nutlin-3a (a small molecule that activates p53 without causing DNA damage), we have previously identified cell lines in which nutlin-3a caused quiescence. Importantly, nutlin-3a caused quiescence by actively suppressing the senescence program (while still causing cell cycle arrest). ...

Up-regulation of telomerase activity is associated with immortalization and unlimited cell division in most cancer cells. Therefore, telomerase represents a particularly attractive target for anticancer therapy. Recent reports have suggested that beta-lapachone (LAPA), the product of the South American Tabebuia avellanedae tree, inhibits growth of tumor cells. However, the underlying ...

Telomerase-negative cancer cells maintain their telomeres by a mechanism known as alternative lengthening of telomeres (ALT) and achieve unlimited replicative potential. A hallmark of ALT cells is the recruitment of telomeres to promyelocytic leukemia (PML) bodies and formation of ALT-associated PML bodies (APBs). Although the exact molecular mechanism of APBs ...

Therapy-induced accelerated cellular senescence (ACS) is a reversible tumor response to chemotherapy that is likely detrimental to the overall therapeutic efficacy of cancer treatment. To further understand the mechanism by which cancer cells can escape the sustained cell cycle arrest in ACS, we established a tissue culture model, in which ...

Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases. Benzyl isothiocyanate (BITC) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables. BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in ...

Originally identified in cultured cells, oncogenic cellular senescence is a growth-arrest mechanism which may inhibit tumor development by limiting the ability of cells to divide. However, literature shows that these cells secrete tumor-inducing and tumor-suppressing proteins leading to poor prognosis. Understanding the progression of oncogenic cellular senescence and associated mechanisms ...

Mammalian aging is thought to be partially caused by the diminished capacity of stem/precursor cells to undergo self-renewing divisions. Although many cell-cycle regulators are involved in this process, it is unknown to what extent cell senescence, first identified as irreversible growth arrest in vitro, contributes to the aging process. Here, ...

Apoptosis and senescence are cellular failsafe programs that counteract excessive mitogenic signaling observed in cancer cells. Melanoma is known for its notorious resistance to apoptotic processes; therefore, senescence, which remains poorly understood in melanomas, can be viewed as a therapeutic alternative. Microphthalmia-associated transcription factor (MITF), in which its M transcript ...

PURPOSE: Senescence and cell death are fail-safe mechanisms protecting against tumorigenesis. Both these forms of cellular response could be induced in cancer cells, thus suppressing tumor progression. Therefore, to fully understand chemotherapeutic effects, not only symptoms of cell death, but also of senescence should be evaluated. Since the involvement of ...

AIM: To determine whether transcriptional reprogramming is capable of reversing the developmental aging of normal human somatic cells to an embryonic state. MATERIALS & METHODS: An isogenic system was utilized to facilitate an accurate assessment of the reprogramming of telomere restriction fragment (TRF) length of aged differentiated cells to that ...

Cellular senescence is an irreversible growth arrest and is presumed to be a natural barrier to tumor development. Like telomere shortening, certain defects in chromosome integrity can trigger senescence; however, the roles of centromere proteins in regulating commitment to the senescent state remains to be established. We examined chromatin structure ...

Telomerase activity is found in various cell types including stem cells, neoplastic cells, and immortalized cells, suggesting a close association with their proliferation capacity. The telomeric repeat amplification protocol (TRAP) has been traditionally used to detect semi-quantitatively the telomerase activity by polyacrylamide gel electrophoresis (PAGE), which is difficult to apply ...

We have previously shown by chromosome transfer technique that chromosome 6 alters the phenotype of a variety of tumour cells and SV40 immortalized cells. We present here the phenotypic effects of the ectopic expression of RNaseT2, a highly conserved ribonuclease encoded by chromosome 6q27, in SV40 immortalized cell lines. We ...

Exceptional genomic stability is one of the hallmarks of mouse embryonic stem (ES) cells. However, the genes contributing to this stability remain obscure. We previously identified Zscan4 as a specific marker for two-cell embryo and ES cells. Here we show that Zscan4 is involved in telomere maintenance and long-term genomic ...

Tetraploidization has been proposed as an intermediate step toward aneuploidy in human cancer but a general mechanism for the induction of tetraploidy during tumorigenesis is lacking. We report that tetraploidization occurs in p53-deficient cells experiencing a prolonged DNA damage signal due to persistent telomere dysfunction. Live-cell imaging revealed that these ...

The telomeric complex, shelterin, plays a critical role in protecting chromosome ends from erosion, and disruption of these complexes can lead to chromosomal instability culminating in cell death or malignant transformation. We reported previously that dominant-negative mutants of one of the telomeric proteins called TIN2 cause death of androgen receptor ...