A role for both RB and p53 in the regulation of human cellular senescence*1

Shay, Jerry W.; Pereira‐Smith, Olivia M.; Wright, Woodring E.

doi:10.1016/0014-4827(91)90453-2

Cited by 676 publications

(454 citation statements)

References 34 publications

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“…Whereas the accumulation of senescent cells in tissues most likely plays a driving role in the aging process (van Deursen, 2014), escape from senescence may lead to cancer (Zou et al ., 2009). Consistent with this hypothesis, replicative senescence is induced by p53 and other checkpoint proteins inactivated in cancers (Shay et al ., 1991; Sugrue et al ., 1997; Schmitt et al ., 2002). Moreover, cancers may originate from cells with telomere attrition (Meeker et al ., 2004) or sometimes with acute telomere losses, due to chromosome fragmentation (Štafa et al ., 2014).…”

Section: Introductionmentioning

confidence: 99%

“…The classical view is that both checkpoint inactivation and telomerase reactivation are required to successfully bypass replicative senescence (Shay et al ., 1991; Wright & Shay, 1995). However, some cancer cells retain relevant checkpoint activity, for example those able to senesce when treated with telomerase inhibitors (Saretzki, 2003).…”

Section: Introductionmentioning

confidence: 99%

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Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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SummaryTelomere attrition is linked to cancer, diabetes, cardiovascular disease and aging. This is because telomere losses trigger further genomic modifications, culminating with loss of cell function and malignant transformation. However, factors regulating the transition from cells with short telomeres, to cells with profoundly altered genomes, are little understood. Here, we use budding yeast engineered to lack telomerase and other forms of telomere maintenance, to screen for such factors. We show that initially, different DNA damage checkpoint proteins act together with Exo1 and Mre11 nucleases, to inhibit proliferation of cells undergoing telomere attrition. However, this situation changes when survivors lacking telomeres emerge. Intriguingly, checkpoint pathways become tolerant to loss of telomeres in survivors, yet still alert to new DNA damage. We show that Rif1 is responsible for the checkpoint tolerance and proliferation of these survivors, and that is also important for proliferation of cells with a broken chromosome. In contrast, Exo1 drives extensive genomic modifications in survivors. Thus, the conserved proteins Rif1 and Exo1 are critical for survival and evolution of cells with lost telomeres.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Rif1 and Exo1 regulate the genomic instability following telomere losses

et al. 2016

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“…However, a striking link between advanced age and increased incidence of cancer is also evident in human and laboratory animals [3]. Inactivation of p53 or pRb tumor suppressor gene is essential to bypass replicative senescence; disruption of only p53 or pRb results in a slight increase of life span, but inactivation of both genes causes somewhat greater increase of life span, however, the cells then enter into crisis and result in cell death [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Loss of p21Sdi1 expression in senescent cells after DNA damage accompanied with increase of miR-93 expression and reduced p53 interaction with p21Sdi1 gene promoter

Choi

Lim

2011

Biochemical and Biophysical Research Communications

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“…Experimentally, suppression of these pathways by the introduction of the SV40 DNA tumor virus large T (LT) oncoprotein or the combined expression of human papillomavirus (HPV) E6 and E7 oncoproteins allows cells to bypass replicative senescence (Shay and Wright 1989;Shay et al 1991). In consonance with these findings, perturbation of both pathways is required to render human cells unable to respond to senescenceinducing stimuli (Serrano et al 1997;Smogorzewska and de Lange 2002).…”

Section: Barriers To Immortalization: Replicative Senescencementioning

confidence: 99%

“…Whereas expression of wild-type LT permits human cells to bypass replicative senescence, expression of LT mutants that bind only p53 or RB does not (Shay et al 1991). Additionally, both the p53-and RB-inactivating capacities of LT are required to allow hTERT-overexpressing cells to avoid RAS-induced growth arrest .…”

Section: Sv40 Lt Antigen: Inhibiting the Rb/p16 Ink4a And P53/p14 Arfmentioning

confidence: 99%

Immortalized cells as experimental models to study cancer

Boehm

Hahn

2004

Cytotechnology

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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.

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A role for both RB and p53 in the regulation of human cellular senescence*1

Cited by 676 publications

References 34 publications

Rif1 and Exo1 regulate the genomic instability following telomere losses

Rif1 and Exo1 regulate the genomic instability following telomere losses

Loss of p21Sdi1 expression in senescent cells after DNA damage accompanied with increase of miR-93 expression and reduced p53 interaction with p21Sdi1 gene promoter

Immortalized cells as experimental models to study cancer

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