A major role of PKC <i>θ</i> and NFκB in the regulation of hTERT in human T lymphocytes

Sheng, Wei-Yun; Chen, Yi-Ru; Wang, Tzu-Chien V.

doi:10.1016/j.febslet.2006.11.044

Cited by 38 publications

(33 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Further studies are needed to assess whether Ets or other transcription factors are involved in ERK1/2-dependent activation of telomerase in B cells induced by LMP1. The observation that NF-B is involved in mediating LMP1-dependent hTERT transactivation in B lymphocytes is consistent with findings obtained with other cellular systems supporting a role for this transcription factor in regulating telomerase (1,50,51). LMP1 was shown to induce telomerase activity in nasopharyngeal carcinoma cells through NF-B activation (11), an effect that was c-Myc dependent, since mutagenesis of c-Myc-responsive E box elements in the hTERT promoter inhibited hTERT transactivation induced by LMP1 (66).…”

Section: Discussionsupporting

confidence: 78%

Latent Membrane Protein 1 of Epstein-Barr Virus Activates the hTERT Promoter and Enhances Telomerase Activity in B Lymphocytes

Terrin

Col

Rampazzo

et al. 2008

J Virol

View full text Add to dashboard Cite

Transformation of primary B lymphocytes by Epstein-Barr virus requires the establishment of a strictly latent infection, the expression of several latent viral proteins, and sustained telomerase activity. Our previous findings indicated that induction of hTERT, the rate-limiting catalytic unit of the telomerase complex, was associated with the expression of the viral latent membrane protein 1 (LMP1). In the present study, we demonstrate that ectopic expression of LMP1 in BJAB and Ramos B cells resulted in an increase of hTERT transcripts, thus suggesting that LMP1 acts at the transcriptional level. This was confirmed by transient expression of a luciferase reporter plasmid containing the hTERT promoter cotransfected with an LMP1-expressing vector or transfected into B cells in which LMP1 expression was inducible. Consistently, silencing of LMP1 by small interfering RNA resulted in a reduction of hTERT transcripts. We also provide evidence indicating that LMP1-induced hTERT activation is independently mediated by NF-B and by mitogen-activated protein kinase and extracellular signal-regulated kinase 1/2 pathways, whereas CD40, Akt, and mTOR signaling has no involvement. Moreover, our results do not support a role for c-Myc in mediating these effects on hTERT, since ectopic expression of LMP1 did not upregulate c-Myc and silencing of this oncogene or E box mutagenesis failed to inhibit LMP1-induced hTERT activation. These findings indicate that LMP1 simultaneously modulates multiple signal transduction pathways in B cells to transactivate the hTERT promoter and enhance telomerase activity, thus confirming the pleiotropic nature of this viral oncoprotein.Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a life-long asymptomatic infection in immunocompetent hosts by colonizing memory B lymphocytes. EBV has a potent transforming ability, being able to efficiently induce blast transformation and uncontrolled proliferation of infected B lymphocytes in vitro. Available evidence, particularly the presence of EBV genomes and the constant expression of viral proteins, strongly supports a relevant role for EBV in the pathogenesis of a wide spectrum of human malignancies, most of which are derived from B lymphocytes (12, 44). Latently EBV-infected B cells may express a defined set of latency genes that include those encoding six nuclear antigens (EBNAs) and three latent membrane proteins (latent membrane protein 1 [LMP1], LMP2A, and LMP2B). Among the EBV latency gene products, LMP1 is considered the strongest oncoprotein, being essential for immortalization of B cells. The N terminus and the six transmembrane domains of the protein form aggregates in the cytoplasmic membrane, allowing LMP1 to act like a constitutively activated receptor (5, 15). Indeed, LMP1 shares functional properties with members of the tumor necrosis factor (TNF) receptor superfamily, particularly CD40, and induces the expression of NF-B through activation of the TNF receptor-associated factor signaling pathway (31,40). Cons...

show abstract

Section: Discussionsupporting

confidence: 78%

Latent Membrane Protein 1 of Epstein-Barr Virus Activates the hTERT Promoter and Enhances Telomerase Activity in B Lymphocytes

Terrin

Col

Rampazzo

et al. 2008

J Virol

View full text Add to dashboard Cite

show abstract

“…In addition, our results were in line with a previous study that NF-κB could be activated by cisplatin in HCC cells (27). C-Myc is a downstream target of NF-κB that upregulates hTERT transcription (30), it remains to be elucidated whether NF-κB may regulate hTERT expression via c-Myc. Our results suggest that c-Myc did not affect cisplatin-induced hTERT expression (Fig.…”

Section: Discussionsupporting

confidence: 81%

Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells

Guo

Ma²,

Zhou³

et al. 2009

Oncol Rep

View full text Add to dashboard Cite

Abstract. The telomerase is specifically activated in most malignant tumors but is usually inactive in normal somatic cells. It has been reported that telomerase has an anti-apoptotic role and up-regulation of telomerase helps cancer cells to be resistant to chemotherapeutic agent-induced cell death. The effect of cisplatin on telomerase activity is complex, and the exact mechanism remains largely unknown. In this study, we found that cisplatin activated telomerase activity and human telomerase reverse transcriptase (hTERT) expression in SMMC7721 human hepatocellular carcinoma cell line. Lowdose cisplatin up-regulated hTERT and NF-κB p65 expression and increased telomerase and NF-κB activity. Inhibition of NF-κB attenuated the hTERT expression and telomerase activity exposed to cisplatin, suggesting that NF-κB is responsible for the cisplatin-induced activation of the hTERT. Furthermore, preincubation of low-dose cisplatin which induced high expression of hTERT help hepatocellular carcinoma SMMC7721 cells survive under the high concentration of anti-cancer drugs. Inhibition of hTERT increased sensitivity of SMMC7721 cells to chemotherapy. Taken together, these results suggested that up-regulation of hTERT expression by low-dose cisplatin is NF-κB-dependent and contributes to chemotherapy resistance in human hepatocellular cancer cells. IntroductionTelomerase is a cellular reverse transcriptase that catalyses the synthesis and extension of telomeric DNA (1,2). This enzyme is specifically activated in most malignant tumors but is usually inactive in normal somatic cells (3,4). The catalytic core of human telomerase is composed of an RNA subunit known as hTER (human telomerase RNA) and a protein subunit named as hTERT (human telomerase reverse transcriptase). Although the RNA subunit (hTR) of the human telomerase complex is constitutively expressed in both tumor and normal somatic tissues, expression of the catalytic subunit (hTERT) correlates with telomerase activity and is a key step of activation of telomerase (5-7). Substantial experiments demonstrate that the transcriptional regulation of hTERT expression represents the primary and rate-limiting step in the activation of telomerase activity in most cells (8)(9)(10)(11). Several studies have indicated that hTERT has an anti-apoptotic activity in addition to its role in telomere length maintenance (12,13).Chemotherapeutic drugs have complex effects on telomerase activity and these complex effects are cell typedependent (14-19). Cisplatin is a DNA cross-linking agent used in the treatment of various tumors including hepatocellular carcinoma (20,21). Human testicular cancer cells treated with lethal doses of cisplatin exhibit decreased telomerase activity (22). In leukemic cells, telomerase activity was also downregulated after treatment with cisplatin (23). Additionally, long-term exposure of colorectal carcinoma cells to cisplatin results in increased telomerase activity (18). However, the exact mechanism of the complex effect of cisplatin on telomerase activity...

show abstract

“…In doing so we identified a number of novel effectors, involving kinases with no previous association with telomere biology. Several kinases that had been previously shown to regulate telomerase were also among the hits, confirming the specificity of the functional read-out of the HTS (6)(7)(8). Moreover several of the identified kinases have been found overexpressed in different human cancers and are now being exploited as potential targets for cancer therapeutics (20)(21)(22)(25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 70%

“…Conversely, c-ABL kinase has been identified as a negative regulator of TA (5). Members of the protein kinase C (PKC) family also phosphorylate hTERT in vitro, induce TA, and stimulate hTERT promoter activity (6,7). The kinase SRC acts as a negative regulator of TA by phosphorylating hTERT in response to oxidative stress and inducing its export from the nucleus (8).…”

Section: Introductionmentioning

confidence: 99%

High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

Cerone

Burgess²,

Naceur-Lombardelli³

et al. 2011

Cancer Research

View full text Add to dashboard Cite

Telomerase is considered an attractive anticancer target on the basis of its common and specific activation in most human cancers. While direct telomerase inhibition is being explored as a therapeutic strategy, alternative strategies to target regulators of telomerase that could disrupt telomere maintenance and cancer cell proliferation are not yet available. Here, we report the findings of a high-throughput functional RNA interference screen to globally profile the contribution of kinases to telomerase activity (TA). This analysis identified a number of novel telomerase modulators, including ERK8 kinase, whose inhibition reduces TA and elicited characteristics of telomere dysfunction. Given that kinases represent attractive drug targets, we addressed the therapeutic implications of our findings, such as demonstrating how limiting TA via kinase blockade could sensitize cells to inhibition of the telomere-associated protein tankyrase. Taken together, our findings suggest novel combinatorial approaches to targeting telomere maintenance as a strategy for cancer therapy. Cancer Res; 71(9); 3328-40. Ó2011 AACR.

show abstract

A major role of PKC θ and NFκB in the regulation of hTERT in human T lymphocytes

Cited by 38 publications

References 41 publications

Latent Membrane Protein 1 of Epstein-Barr Virus Activates the hTERT Promoter and Enhances Telomerase Activity in B Lymphocytes

Latent Membrane Protein 1 of Epstein-Barr Virus Activates the hTERT Promoter and Enhances Telomerase Activity in B Lymphocytes

Up-regulation of hTERT expression by low-dose cisplatin contributes to chemotherapy resistance in human hepatocellular cancer cells

High-Throughput RNAi Screening Reveals Novel Regulators of Telomerase

Contact Info

Product

Resources

About