Human Endothelial Cell Life Extension by Telomerase Expression

Yang, Jiwei; Chang, Edwin; Cherry, Athena M.; Bangs, Charles D.; Oei, Yoko; Bodnár, Andrea; Bronstein, A.D.; Chiu, Choy‐Pik; Herron, G. Scott

doi:10.1074/jbc.274.37.26141

Cited by 454 publications

(365 citation statements)

References 66 publications

Supporting

Mentioning

331

Contrasting

Unclassified

Order By: Relevance

“…Although ectopic hTERT expression prevents telomere erosion and facilitates proliferation in some cell types without induction of transformation, [5][6][7][8][9][10] it has been reported that mice with transgenic expression of mouse TERT are susceptible to tumor development. 42 To some extent, telomerase activity may be associated with tumor development as some tumor cells show elevated telomerase activity and can still maintain long telomeres without pronounced telomerase activity.…”

Section: Ectopic Telomerase Expression Does Not Lead To Growth Transfmentioning

confidence: 99%

“…4 Ectopic hTERT expression in various human cell types including T lymphocytes reconstitutes telomerase activity, prevents telomere erosion and extends the life span of these cells without altering their functional and phenotypic properties. [5][6][7][8][9][10] Although antigen-specific T cells are rescued from apoptosis during primary activation by telomerase expression, repeated antigenic stimulation leads to telomere shortening due to the loss of telomerase inducibility. 11,12 T-cell memory erosion has an important role in chronic infections related to severe pathology, especially in elderly individuals and in immunosuppressed patients.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

2010

View full text Add to dashboard Cite

The rhadinovirus herpesvirus saimiri (HVS) as a gene delivery vector allows large DNA insertions and long-termed gene expression. In the case of T-cell transduction, such vectors use the viral transformation-associated genes of HVS C488 for T-cell amplification. In this report, we investigated whether the gene for the catalytic telomerase subunit human telomerase reverse transcriptase (hTERT) can substitute for the transformation-associated genes in rhadinoviral T-cell transduction and amplification. By using virus mutants generated by en passant mutagenesis from bacterial artificial chromosomes, we observed a very early and functional transgene expression even by virus mutants without transformation-associated genes. The markers of T-cell transformation by HVS, namely CD2 hyperreactivity, overexpression of interleukin-26, and of the tyrosine kinase Lyn could neither be induced nor enhanced by ectopic hTERT expression. When the viral transformation-associated genes were replaced by the hTERT gene, it was not sufficient for growth transformation, although hTERT was efficiently transduced and functionally expressed by the rhadinovirus vector. Thus, the transformation-associated proteins StpC and Tip are responsible for the T-cell phenotype after transduction by HVS and, additionally, modulate telomerase activity independently of hTERT expression.

show abstract

Section: Ectopic Telomerase Expression Does Not Lead To Growth Transfmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

2010

View full text Add to dashboard Cite

show abstract

“…In addition, cells from older individuals exhibit a more limited replicative capacity and shorter telomere lengths than cells derived from younger individuals (Harley et al 1990;Hastie et al 1990). Ectopic expression of hTERT restores constitutive telomerase activity, stabilizes telomeres and directly immortalizes some human cell types including human diploid foreskin fibroblasts, retinal pigment epithelial cells (Bodnar et al 1998;Vaziri and Benchimol 1998), vascular endothelial cells (Yang et al 1999), mesothelial cells (Dickson et al 2000) and osteoblasts (Xiaoxue et al 2004). These observations support a model in which progressive telomere attrition triggers replicative senescence.…”

Section: Barriers To Immortalization: Replicative Senescencementioning

confidence: 99%

“…In endothelial cells, telomere restriction fragment (TRF) lengths at the onset of replicative senescence are $5.7 kbp , yet human umbilical vein endothelial cells immortalized by the expression of hTERT bypass replicative senescence with TRF lengths of 2-2.5 kbp (Yang et al 1999). These observations suggest that a specific telomere length does not trigger replicative senescence.…”

Section: Barriers To Immortalization: Replicative Senescencementioning

confidence: 99%

Immortalized cells as experimental models to study cancer

Boehm

Hahn

2004

Cytotechnology

View full text Add to dashboard Cite

The development of cancer is a multi-step process in which normal cells sustain a series of genetic alterations that together program the malignant phenotype. Much of our knowledge of cancer biology results from the detailed study of specimens and cell lines derived from patient tumors. While these approaches continue to yield critical information regarding the identity, number, and types of alterations found in human tumors, further progress in understanding the molecular basis of malignant transformation depends upon the generation and use of increasingly sophisticated experimental models of cancer. Over the past several years, the recognition that telomeres and telomerase play essential roles in regulating cell lifespan now permits the development of new models of human cancer. Here we review recent progress in the use of immortalized human cells as a foundation for understanding the molecular basis of cancer.Abbreviations: ALT -alternative lengthening of telomeres; HEK -human embryonic kidney; HMEChuman mammary epithelial cell; HPV -human papillomavirus; hTERT -human telomerase reverse transcriptase; LT -SV40 Large T antigen; PD -population doubling; PP2A -protein phosphatase 2A; RalGEF -Ral guanine nucleotide exchange factor; RAS -activated H-Ras allele; shRNA -short hairpin RNA; ST -SV40 small t antigen; TRF -telomere restriction fragment.

show abstract

“…Previous reports have suggested that exogenous expression of the catalytic component of telomerase (TERT) is capable of immortalizing many different human cell types (fibroblasts, retinal pigmented epithelial cells, vascular endothelial cells and mesothelial cells) without the need for additional genetic alterations (Bodnar et al, 1998;Yang et al, 1999;Dickson et al, 2000). Several human epithelial cell types (keratinocytes, mammary epithelial cells, bladder urothelial cells and prostatic epithelial cells), however, have been shown to experience a telomere-independent growth arrest that is enforced by the p16/pRb pathway (Foster and Galloway, 1996;Brenner et al, 1998;Puthenveettil et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Methylation of the p16INK4a promoter region in telomerase immortalized human keratinocytes co-cultured with feeder cells

et al. 2006

View full text Add to dashboard Cite

Human keratinocytes grown in co-culture with fibroblast feeder cells have an extended in vitro lifespan and delayed accumulation of the tumor suppressor protein p16 INK4a when compared to the same cells grown on tissue culture plastic alone. Previous studies have indicated that human keratinocytes can be immortalized by telomerase activity alone when grown in co-culture with feeder cells, suggesting that loss of the p16 INK4a /Rb pathway is not required for immortalization. Using two independent human keratinocyte cell strains, we found that exogenous telomerase expression and co-culture with feeder cells results in efficient extension of lifespan without an apparent crisis. However, when these cells were transferred from the co-culture environment to plastic alone they experienced only a brief period of slowed growth before continuing to proliferate indefinitely. Examination of immortal cell lines demonstrated p16 INK4a promoter methylation had occurred in both the absence and presence of feeder cells. Reintroduction of p16 INK4a into immortal cell lines resulted in rapid growth arrest. Our results suggest that p16 INK4a /Rb-induced telomereindependent senescence, although delayed in the presence of feeders, still provides a proliferation barrier to human keratinocytes in this culture system and that extended culture of telomerase-transduced keratinocytes on feeders can lead to the methylation of p16 INK4a .

show abstract

Human Endothelial Cell Life Extension by Telomerase Expression

Cited by 454 publications

References 66 publications

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

Rhadinovirus vector-derived human telomerase reverse transcriptase expression in primary T cells

Immortalized cells as experimental models to study cancer

Methylation of the p16INK4a promoter region in telomerase immortalized human keratinocytes co-cultured with feeder cells

Contact Info

Product

Resources

About