Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype

Jiang, Xu‐Rong; Jimenez, Gretchen; Chang, Edwin; Frolkis, Maria; Kusler, Brenda; Sage, Marijke; Beeche, Michelle; Bodnár, Andrea; Wahl, Geoffrey M.; Tlsty, Thea D.; Chiu, Choy‐Pik

doi:10.1038/5056

Cited by 595 publications

(388 citation statements)

References 22 publications

(22 reference statements)

Supporting

Mentioning

361

Contrasting

Unclassified

Order By: Relevance

“…Some authors have noted that hTERT þ cells express a normal cell-cycle arrest and checkpoint protein response to specific challenges including DNA damaging agents (including chromium) (Jiang et al, 1999;Morales et al, 1999;Pritchard et al, 2001;Wood et al, 2001;Gorbunova et al, 2002). In contrast, other authors have reported that there is a loss of p16INK4a and hyperphosphorylation of pRb in hTERT þ cells (Tsutsui et al, 2002;Piboonniyom et al, 2003) and in one cell line a mutation in p53 and abnormal G1 checkpoint (Noble et al, 2004).…”

Section: Metal-induced Genomic Instabilitymentioning

confidence: 99%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

View full text Add to dashboard Cite

There is currently a great interest in delayed chromosomal and other damaging effects of low-dose exposure to a variety of pollutants which appear collectively to act through induction of stress-response pathways related to oxidative stress and ageing. These have been studied mostly in the radiation field but evidence is accumulating that the mechanisms can also be triggered by chemicals, especially heavy metals. Humans are exposed to metals, including chromium (Cr) (VI) and vanadium (V) (V), from the environment, industry and surgical implants. Thus, the impact of low-dose stress responses may be larger than expected from individual toxicity projections. In this study, a short (24 h) exposure of human fibroblasts to low doses of Cr (VI) and V (V) caused both acute chromosome damage and genomic instability in the progeny of exposed cells for at least 30 days after exposure. Acutely, Cr (VI) caused chromatid breaks without aneuploidy while V (V) caused aneuploidy without chromatid breaks. The longerterm genomic instability was similar but depended on hTERT positivity. In telomerase-negative hTERTÀ cells, Cr (VI) and V (V) caused a long lasting and transmissible induction of dicentric chromosomes, nucleoplasmic bridges, micronuclei and aneuploidy. There was also a long term and transmissible reduction of clonogenic survival, with an increased b-galactosidase staining and apoptosis. This instability was not present in telomerasepositive hTERT þ cells. In contrast, in hTERT þ cells the metals caused a persistent induction of tetraploidy, which was not noted in hTERTÀ cells. The growth and survival of both metal-exposed hTERT þ and hTERTÀ cells differed if they were cultured at subconfluent levels or plated out as colonies. Genomic instability is considered to be a driving force towards cancer. This study suggests that the type of genomic instability in human cells may depend critically on whether they are telomerase-positive or -negative and that their sensitivities to metals could depend on whether they are clustered or diffuse.

show abstract

Section: Metal-induced Genomic Instabilitymentioning

confidence: 99%

Effects of hTERT on metal ion-induced genomic instability

et al. 2006

View full text Add to dashboard Cite

show abstract

“…However, we and others have described earlier that the only step required for the immortalization of somatic cells is activation of telomerase (Jiang et al, 1999;Morales et al, 1999;Li et al, 2007). In our study, we generated hTERT immortalized epithelial cell lines without disruption of pRb and p53 function.…”

mentioning

confidence: 90%

A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells

Kocher

Salako

et al. 2008

Oncogene

View full text Add to dashboard Cite

The receptor for macrophage colony-stimulating factor 1 receptor (CSF1R) is a product of the proto-oncogene c-fms and a member of the class III transmembrane tyrosine kinase receptor family. Earlier, we described increased mRNA expression of CSF1R in human telomerase reverse transcriptase (hTERT) immortalized human ovarian surface epithelial (IOSE) cell lines derived from a single donor. Here, we further describe that CSF1R is upregulated at both the mRNA and protein level in hTERT immortalized human normal OSE cells from two different donors and in hTERT immortalized human pancreatic ductal epithelial cells. CSF1R was not upregulated in hTERT immortalized epithelial clones that subsequently underwent senescence or in immortalized fibroblasts. Upon stimulation by the CSF1R ligand CSF1, the immortalized epithelial cell lines showed rapid internalization of CSF1R with concomitant down-modulation and colocalization of phosphorylated NFjBp65 with hTERT protein, hTERT translocation into the nucleus and the binding of c-Myc to the hTERT promoter region. Reducing the expression of CSF1R using short hairpin interfering RNA abolished these effects and also decreased cell survival and the number of population doublings under suboptimal culture conditions. The telomerase inhibitor GRN163L confirmed a role for telomerase in the cleavage of the intracellular domain of CSF1R. On the basis of these findings, we suggest that CSF1R may be a critical factor facilitating hTERT immortalization of epithelial cells.

show abstract

“…Primary dermal fibroblasts from an XP-V patient (GM3617) and a normal control (GM5659D) were immortalized with the catalytic subunit of telomerase (hTERT) which does not disrupt normal cell cycle checkpoints [30][31][32] [33] and cells were designated GM5659DT and GM3617T. We employed a gene knockdown approach using RNA interference directed against a target sequence of p53 [29].…”

Section: P53-suppressed Xp-v and Normal Fibroblasts[30]mentioning

confidence: 99%

p53 suppression overwhelms DNA polymerase η deficiency in determining the cellular UV DNA damage response

et al. 2007

View full text Add to dashboard Cite

Xeroderma pigmentosum variant (XP-V) cells lack the damage-specific DNA polymerase η and have normal excision repair but show defective DNA replication after UV irradiation. Previous studies using cells transformed with SV40 or HPV16 (E6/E7) suggested that the S-phase response to UV damage is altered in XP-V cells with non-functional p53. To investigate the role of p53 directly we targeted p53 in normal and XP-V fibroblasts using short hairpin RNA. The shRNA reduced expression of p53, and the downstream cell cycle effector p21, in control and UV irradiated cells. Cells accumulated in late S phase after UV, but after down-regulation of p53 they accumulated earlier in S. Cells in which p53 was inhibited showed ongoing genomic instability at the replication fork. Cells exhibited high levels of UV induced S-phase γH2Ax phosphorylation representative of exposed single strand regions of DNA and foci of Mre11/Rad50/Nbs1 representative of double strand breaks. Cells also showed increased variability of genomic copy numbers after long-term inhibition of p53. Inhibition of p53 expression dominated the DNA damage response. Comparison with earlier results indicates that in virally transformed cells cellular targets other than p53 play important roles in the UV DNA damage response.

show abstract

Telomerase expression in human somatic cells does not induce changes associated with a transformed phenotype

Cited by 595 publications

References 22 publications

Effects of hTERT on metal ion-induced genomic instability

Effects of hTERT on metal ion-induced genomic instability

A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells

p53 suppression overwhelms DNA polymerase η deficiency in determining the cellular UV DNA damage response

Contact Info

Product

Resources

About