Transformation of normal human cells in the absence of telomerase activation

Seger, Yvette R.; Garcı́a-Cao, Marta; Piccinin, Sara; Cunsolo, Crocifissa Lo; Doglioni, Claudio; Blasco, Marı́a A.; Hannon, Gregory J.; Maestro, Roberta

doi:10.1016/s1535-6108(02)00183-6

Cited by 144 publications

(157 citation statements)

References 60 publications

Supporting

Mentioning

139

Contrasting

Unclassified

Order By: Relevance

“…Because NAC was effective in blocking oncogene-induced chromosomal instability, it is likely that an additional stochastic event occurred in vivo for this single tumor to have formed. It is noteworthy that transformation of cells by coexpressing two or more genetic elements resulted in tumor cell populations that were polyclonal (Hahn et al 1999;Seger et al 2002). However, the pervasive nature in which oncogenic Ras and E1A induce chromosomal instability and karyotypic change demonstrates that tumor cells can undergo additional genetic alterations but still be polyclonal.…”

Section: Chromosomally Stable Serum-free Mouse Embryo Fibroblasts Arementioning

confidence: 99%

“…An extensive body of evidence has shown that several cooperating genetic elements can lead to the in vitro transformation of rodent and human cells (Land et al 1983;Ruley 1983;Hahn et al 1999;Rich et al 2001;MacKenzie et al 2002;Seger et al 2002). However, it has been more difficult to define the contribution of gross genetic alterations that are characteristic of nearly every tumor cell.…”

Section: Oncogenes Collaborate With Chromosomal Instability During Tumentioning

confidence: 99%

“…The transformation of primary human cells has now been achieved by coexpressing a combination of three different genetic elements such as H-RasV12, SV40 early region, and hTERT (Hahn et al 1999;Rich et al 2001;MacKenzie et al 2002) or H-RasV12, E1A, and Mdm2 (Seger et al 2002). In fact, Weinberg and colleagues (Hahn et al 1999;Zimonjic et al 2001) were able to transform human embryonic kidney (HEK) cells with three distinct genetic elements without widespread genomic instability.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation

Woo¹,

Poon²

2004

Genes Dev.

114

View full text Add to dashboard Cite

Most cancer cells are aneuploid. The chromosomal instability hypothesis contends that aneuploidy is the catalyst for transformation, whereas the gene mutation hypothesis asserts that cancer is driven by mutations to proto-oncogenes and tumor-suppressor genes, with the aneuploidy a side effect of tumorigenesis. Because genotoxic stress induced by "culture shock" can obscure the transforming potential of exogenous genes, we cultured wild-type and p53 −/− mouse embryo fibroblasts in a more physiological (serum-free) environment. Under these conditions, the cells were immortal and, more importantly, chromosomally stable. Expression of oncogenic H-RasV12 did not induce senescence, but sensitized these cells to p53-dependent apoptosis. In addition, H-RasV12 induced chromosomal instability, as well as accumulation and phosphorylation of p53. Significantly, whereas cells grown under standard conditions could be transformed by coexpression of H-RasV12 and E1A, the chromosomally stable cells were refractory to transformation, as measured by anchorage-independent growth and tumor formation in nude mice. These oncogenes required a third genetic alteration that abolished the p53 pathway to create a permissive environment that promotes rapid chromosomal instability and transformation. Oncogene-induced chromosomal instability and transformation was attenuated by antioxidants. These data indicate that chromosomal instability could be a catalyst for oncogenic transformation, and bring together aspects of the chromosomal instability hypothesis and the gene mutation hypothesis for tumorigenesis.[Keywords: Chromosomal instability; oncogenic Ras; p53; transformation] Supplemental material is available at http://www.genesdev.org.

show abstract

Section: Chromosomally Stable Serum-free Mouse Embryo Fibroblasts Arementioning

confidence: 99%

Section: Oncogenes Collaborate With Chromosomal Instability During Tumentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation

Woo¹,

Poon²

2004

Genes Dev.

114

View full text Add to dashboard Cite

show abstract

“…Recent results, however, suggest that telomerase activity is not an obligate requirement for initial tumor formation under certain circumstances (Seger et al 2002). The co-expression of the adenovirus E1A oncoprotein and RAS suffices to induce anchorage-independent growth of BJ cells in soft agar.…”

Section: Htertmentioning

confidence: 99%

“…However, these cells undergo crisis either after extended passaging in vitro (40-50 PDs) or after explantation into culture. Cells which survive this period of crisis show telomerase activity (Seger et al 2002).…”

Section: Htertmentioning

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

Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

2018

View full text Add to dashboard Cite

Expression of the class IIa HDACs is frequently altered in different human cancers. In mouse models these transcriptional repressors can trigger transformation, acting as bona fide oncogenes. Whether class IIa HDACs also exhibit transforming activities in human cells is currently unknown. We infected primary human fibroblasts with retroviruses to investigate the transforming activity of HDAC4 in cooperation with well‐known oncogenes. We have discovered that HDAC4 triple mutant (S246A, S467A, S632A) (HDAC4‐TM), a nuclear resident version of the deacetylase, triggers TP53 stabilization and OIS (oncogene‐induced senescence). Unlike RAS, HDAC4‐induced OIS was TP53‐dependent and characterized by rapid cell cycle arrest and accumulation of an unusual pattern of γH2AX‐positive foci. The inactivation of both TP53 and of the retinoblastoma (pRb) tumor suppressors, as induced by the viral oncogenes large and small T of SV40, triggers anchorage‐independent growth in RAS, HDAC4‐TM and, to a lesser extent, in HDAC4‐wild type (WT)‐expressing cells. Our results suggest an oncogenic function of class IIa HDACs in human cells, and justify further efforts to discover and evaluate isoform‐specific inhibitors of these epigenetic regulators from a therapeutic perspective.

show abstract

Transformation of normal human cells in the absence of telomerase activation

Cited by 144 publications

References 60 publications

Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation

Activated oncogenes promote and cooperate with chromosomal instability for neoplastic transformation

Immortalized cells as experimental models to study cancer

Unscheduled HDAC4 repressive activity in human fibroblasts triggers TP53‐dependent senescence and favors cell transformation

Contact Info

Product

Resources

About