scholarly journals Telomerase Gene Therapy: A Remission Towards Cancer

2021 ◽  
Author(s):  
Sameer Quazi
Keyword(s):  
Gene Therapy ◽  
Cancer Cells ◽  
Chromosomal Instability ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Telomerase Activity ◽  
Genetic Mutation ◽  
Telomere Attrition ◽  
Animal Trials ◽  
Clinical Advances

Telomerase is an enzyme which is culpable for the aliment and stability of telomeres. It also maintains the genomic integrity and chromosomal stability. The progressive shortening of telomeres may cause chromosomal instability and alternation in the telomerase. It may cause telomere attrition which can lead to oncogenic incidence in human. Cancer is a disease which is induced by genetic alternations in genes. The genetic mutation within the hTERT is a common type of scenario which is generally found above 90 percent of cancer. In cancer, the length of telomere and the activity of telomerase are very important for cancer cells to proliferate and also for the survival of tumors. Cancer cells regulate through several pathways to increase telomerase activity. There have been several advancements developed to inhibit the telomerase activity in cancer cell but the repercussion of those has demonstrated many adverse effects. Research on AAVs mediated telomerase gene therapy has demonstrated prominent outcomes in animal trials. Thus, it has the potential to bring significance shine in the telomerase cancer therapeutics. Here, in this review article we have analyzed studies related to telomerase gene therapeutics to cure cancer. We also have summarized the telomerase function and mechanism of action to cause cancer. Moreover, other current development in the clinical advances of telomerase inhibition in cancer is described.

scholarly journals Control of MYC-dependent apoptotic threshold by a co-amplified ubiquitin E3 ligase UBR5

2019 ◽  
Author(s):  
Xi Qiao ◽  
Ying Liu ◽  
Maria Llamazares Prada ◽  
Abhishekh Gupta ◽  
Alok Jaiswal ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Cells ◽  
Ubiquitin Ligase ◽  
Breast Cancer Cells ◽  
Human Cancer ◽  
Cancer Therapeutics ◽  
Cancer Tissue ◽  
Basal Type

AbstractMYC protein expression has to be tightly controlled to allow for maximal cell proliferation without inducing apoptosis. Here we discover UBR5 as a novel MYC ubiquitin ligase and demonstrate how it functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 effects on MYC protein stability are independent on N-terminal FBW7 degron of MYC. Endogenous UBR5 inhibition induces MYC protein expression and activates MYC target genes. Moreover, UBR5 governs MYC-dependent phenotypes in vivo in Drosophila. In cancer cells, UBR5-mediated MYC protein suppression diminishes cell killing activity of cancer therapeutics. Further, we demonstrate that UBR5 dominates MYC protein expression at the single-cell level in human basal-type breast cancer tissue. Myc and Ubr5 are co-amplified in MYC-driven human cancer types, and UBR5 controls MYC-mediated apoptotic threshold in co-amplified basal type breast cancer cells. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC protein expression in vivo. Clinically, expression of UBR5 may be important for protection of breast cancer cells from drug-induced, and MYC-dependent, apoptosis.

Retinoic acid-induced downmodulation of telomerase activity in human cancer cells

2005 ◽  
Vol 79 (2) ◽  
pp. 108-117 ◽  
Author(s):  
Xiaodong Xiao ◽  
Igor A. Sidorov ◽  
Jennifer Gee ◽  
Richard A. Lempicki ◽  
Dimiter S. Dimitrov
Keyword(s):  
Retinoic Acid ◽  
Cancer Cells ◽  
Human Cancer ◽  
Telomerase Activity ◽  
Human Cancer Cells

scholarly journals Dormant replication origin firing links replication stress to whole chromosomal instability in human cancer

2021 ◽  
Author(s):  
Ann-Kathrin Schmidt ◽  
Nicolas Boehly ◽  
Xiaoxiao Zhang ◽  
Benjamin O. Slusarenko ◽  
Magdalena Hennecke ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Chromosomal Instability ◽  
Replication Origin ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Replication Stress ◽  
S Phase ◽  
Origin Firing ◽  
Human Cancer Cells ◽  
Chromosome Missegregation

Chromosomal instability (CIN) is a hallmark of cancer and comprises structural CIN (S-CIN) and whole chromosome instability (W-CIN). Replication stress (RS), a condition of slowed or stalled DNA replication during S phase, has been linked to S-CIN, whereas defects in mitosis leading to chromosome missegregation and aneuploidy can account for W-CIN. It is well established that RS can activate additional replication origin firing that is considered as a rescue mechanism to suppress chromosomal instability in the presence of RS. In contrast, we show here that an increase in replication origin firing during S phase can contribute to W-CIN in human cancer cells. Increased origin firing can be specifically triggered by overexpression of origin firing genes including GINS1 and CDC45, whose elevated expression significantly correlates with W-CIN in human cancer specimens. Moreover, endogenous mild RS present in cancer cells characterized by W-CIN or modulation of the origin firing regulating ATR-CDK1-RIF1 axis induces dormant origin firing, which is sufficient to trigger chromosome missegregation and W-CIN. Importantly, chromosome missegregation upon increased dormant origin firing is mediated by increased microtubule growth rates leading to the generation of lagging chromosomes in mitosis, a condition prevalent in chromosomally unstable cancer cells. Thus, our study identified increased or dormant replication origin firing as a hitherto unrecognized, but cancer-relevant trigger for chromosomal instability.

scholarly journals Antitumor Effect of a Novel Adeno-associated Virus Vector Targeting to Telomerase Activity in Tumor Cells

2004 ◽  
Vol 36 (7) ◽  
pp. 492-500 ◽  
Author(s):  
Yi-Gang Wang ◽  
Jin-Hui Wang ◽  
Yan-Hong Zhang ◽  
Qing Gu ◽  
Xin-Yuan Liu
Keyword(s):  
Cancer Cells ◽  
Antitumor Effect ◽  
Human Cancer ◽  
Telomerase Activity ◽  
Human Interferon ◽  
Human Telomerase Reverse Transcriptase ◽  
Adeno Associated Virus ◽  
Human Cancer Cells ◽  
Vector Targeting

Abstract Telomerase activity is a wide tumor marker. Human telomerase reverse transcriptase (hTERT), the catalytic subunit of the telomerase, is transcriptionally upregulated exclusively in about 90% of cancer cells. In this study, we constructed a novel adeno-associated virus (AAV) vector containing the human interferon-β (hIFN-β) gene under the control of hTERT promoter (AAV-hTERT-hIFN-β) and investigated its antitumor effect against various human cancer cells in vitro. AAV-hTERT-hIFN-β displayed cancer-specific hIFN-β expression and cytotoxicity. The cytotoxic ratio was positively correlated with the time length of infection. AAV-hTERT-hIFN-β-mediated apoptotic morphology was observed by transmission electron microscopy. Flow cytometry assay also revealed that the cytotoxicity of AAV-hTERT-hIFN-β was mainly an apoptotic process. These data indicate that AAV in combination with hTERT-mediated therapeutic gene expression may open new possibilities for long-lasting and targeting gene therapy of varieties of cancers.

scholarly journals Template activating factor-I epigenetically regulates the TERT transcription in human cancer cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kohsuke Kato ◽  
Atsushi Kawaguchi ◽  
Kyosuke Nagata
Keyword(s):  
Cancer Cells ◽  
Transcriptional Activation ◽  
Human Cancer ◽  
Tumor Development ◽  
Telomerase Activity ◽  
Transcription Start ◽  
Cpg Dinucleotides ◽  
Human Cancer Cells ◽  
Factor I ◽  
Repeat Dna

AbstractTelomere, the terminus of linear chromosome in eukaryotes, is composed of specific repeat DNA which is mainly synthesized by a protein complex called telomerase. The maintenance of telomere DNA is important for unlimited proliferative capacity of cancer cells. The telomerase activity is controlled by the expression level of telomerase reverse transcriptase (TERT), a catalytic unit of telomerase, in some species including human. Therefore, to reveal the regulatory mechanisms of the transcription of TERT gene is important for understanding the tumor development. We found that template activating factor-I (TAF-I), a multifunctional nuclear protein, is involved in the transcriptional activation of TERT for the maintenance of telomere DNA in HeLa cells. TAF-I maintains the histone H3 modifications involved in transcriptional activation and hypomethylated cytosines in CpG dinucleotides around the transcription start site (TSS) in the TERT gene locus. Collectively, TAF-I is involved in the maintenance of telomere DNA through the regulation of TERT transcription, then consequently the occurrence and/or recurrence of cancer cells.

scholarly journals Adaptive Resistance to an Inhibitor of Chromosomal Instability in Human Cancer Cells

Cell Reports ◽  
2016 ◽  
Vol 17 (7) ◽  
pp. 1755-1763 ◽  
Author(s):  
Bernardo Orr ◽  
Lama Talje ◽  
Zhexian Liu ◽  
Benjamin H. Kwok ◽  
Duane A. Compton
Keyword(s):  
Cancer Cells ◽  
Chromosomal Instability ◽  
Human Cancer ◽  
Adaptive Resistance ◽  
Human Cancer Cells

scholarly journals The p53/p73 - p21CIP1 tumor suppressor axis guards against chromosomal instability by restraining CDK1 in human cancer cells

Oncogene ◽  
2020 ◽  
Author(s):  
Ann-Kathrin Schmidt ◽  
Karoline Pudelko ◽  
Jan-Eric Boekenkamp ◽  
Katharina Berger ◽  
Maik Kschischo ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cancer Cells ◽  
Tumor Suppressor Genes ◽  
Chromosomal Instability ◽  
Target Gene ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Microtubule Assembly ◽  
Cdk Inhibitor ◽  
Human Cancer Cells

Abstract Whole chromosome instability (W-CIN) is a hallmark of human cancer and contributes to the evolvement of aneuploidy. W-CIN can be induced by abnormally increased microtubule plus end assembly rates during mitosis leading to the generation of lagging chromosomes during anaphase as a major form of mitotic errors in human cancer cells. Here, we show that loss of the tumor suppressor genes TP53 and TP73 can trigger increased mitotic microtubule assembly rates, lagging chromosomes, and W-CIN. CDKN1A, encoding for the CDK inhibitor p21CIP1, represents a critical target gene of p53/p73. Loss of p21CIP1 unleashes CDK1 activity which causes W-CIN in otherwise chromosomally stable cancer cells. Consequently, induction of CDK1 is sufficient to induce abnormal microtubule assembly rates and W-CIN. Vice versa, partial inhibition of CDK1 activity in chromosomally unstable cancer cells corrects abnormal microtubule behavior and suppresses W-CIN. Thus, our study shows that the p53/p73 - p21CIP1 tumor suppressor axis, whose loss is associated with W-CIN in human cancer, safeguards against chromosome missegregation and aneuploidy by preventing abnormally increased CDK1 activity.

scholarly journals CRISPR/Cas9-Mediated TERT Disruption in Cancer Cells

2020 ◽  
Vol 21 (2) ◽  
pp. 653 ◽  
Author(s):  
Luan Wen ◽  
Changzhi Zhao ◽  
Jun Song ◽  
Linyuan Ma ◽  
Jinxue Ruan ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Tumor Cells ◽  
Gene Editing ◽  
Therapeutic Option ◽  
Telomerase Activity ◽  
Telomere Attrition ◽  
Tert Gene ◽  
Cancer Cell Survival

Mammalian telomere lengths are primarily regulated by telomerase, a ribonucleoprotein consisting of a reverse transcriptase (TERT) and an RNA subunit (TERC). TERC is constitutively expressed in all cells, whereas TERT expression is temporally and spatially regulated, such that in most adult somatic cells, TERT is inactivated and telomerase activity is undetectable. Most tumor cells activate TERT as a mechanism for preventing progressive telomere attrition to achieve proliferative immortality. Therefore, inactivating TERT has been considered to be a promising means of cancer therapy. Here we applied the CRISPR/Cas9 gene editing system to target the TERT gene in cancer cells. We report that disruption of TERT severely compromises cancer cell survival in vitro and in vivo. Haploinsufficiency of TERT in tumor cells is sufficient to result in telomere attrition and growth retardation in vitro. In vivo, TERT haploinsufficient tumor cells failed to form xenograft after transplantation to nude mice. Our work demonstrates that gene editing-mediated TERT knockout is a potential therapeutic option for treating cancer.

Sign in / Sign up

Export Citation Format

Share Document