Direct evidence from siRNA-directed “knock down” that p16INK4a is required for human fibroblast senescence and for limiting ras-induced epithelial cell proliferation

Bond, Jane A.; Jones, Christopher J.; Haughton, Michele Fleur; DeMicco, Catherine; Kipling, David; Wynford-Thomas, David

doi:10.1016/j.yexcr.2003.09.021

Cited by 44 publications

(28 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As cell type diversity in lifespan regulation may determine the pattern of gene alterations in the tumours that arise in that tissue, it was not unexpected that p53 and Rb pathway-dependent proliferative barriers were identified in NHUC, as at least half of UCC cases contain p53 mutations (Markl and Jones, 1998) and most have inactivation of the p16/Rb pathway (Sarkar et al, 2000). Senescence of NHUC, as in fibroblasts, (Bond et al, 2004) was accompanied by upregulation of p16 expression. However, unlike the situation in fibroblasts (Alcorta et al, 1996), upregulation of p21 and dramatic shortening of mean telomere length were not observed, possibly because NHUC proliferating in vitro express low levels of telomerase .…”

Section: Discussionmentioning

confidence: 94%

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

et al. 2006

View full text Add to dashboard Cite

The CDKN2A locus is frequently inactivated in urothelial cell carcinoma (UCC), yet how this alteration contributes to bladder tumorigenesis is not known. Although most UCC express telomerase, inactivation of the p16/Rb pathway is generally required for in vitro immortalisation. This and the involvement of p16 in senescence of normal human urothelial cells (NHUC) suggest that CDKN2A deletion may aid bypass of senescence and allow immortalisation. CDKN2A encodes p16 and p14 ARF and therefore inactivation of this locus can disrupt both the Rb and p53 tumour suppressor pathways. Retrovirusmediated transduction was used to specifically modulate the p16/Rb and/or p53 tumour suppressor pathways in NHUC and to express human telomerase reverse transcriptase (hTERT). Expression of hTERT bypassed Rb and p53 pathway-dependent barriers to proliferation and immortalised NHUC. TERT-NHUC had normal karyotypes, were non-tumorigenic and unexpectedly retained CDKN2A. Thus, the phenotypic significance of inactivation of CDKN2A in UCC may not be solely related to bypass of senescence. Phenotypic assays in human urothelial cells have relied on cell strains derived from invasive tumours or NHUC immortalised by expression of SV40-large T. The production of genetically normal but immortal NHUC lines now provides a valuable platform for experiments to examine the timing and combination of events necessary for UCC tumorigenesis.

show abstract

Section: Discussionmentioning

confidence: 94%

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

et al. 2006

View full text Add to dashboard Cite

show abstract

“…INK4a rescued H-Ras G12V expressing thyrocytes from senescence (Bond et al 2004), suggesting that the OIS programme might not be universal in different genetic contexts.…”

Section: Ink4amentioning

confidence: 99%

Evidence of oncogene-induced senescence in thyroid carcinogenesis

Vizioli

Possik

Tarantino

et al. 2011

Endocrine-Related Cancer

View full text Add to dashboard Cite

Oncogene-induced senescence (OIS) is a growth arrest triggered by the enforced expression of cancer-promoting genes and acts as a barrier against malignant transformation in vivo. In this study, by a combination of in vitro and in vivo approaches, we investigate the role of OIS in tumours originating from the thyroid epithelium. We found that expression of different thyroid tumour-associated oncogenes in primary human thyrocytes triggers senescence, as demonstrated by the presence of OIS hallmarks: changes in cell morphology, accumulation of SA-b-Gal and senescence-associated heterochromatic foci, and upregulation of transcription of the cyclindependent kinase inhibitors p16INK4a and p21 CIP1 . Furthermore, immunohistochemical analysis of a panel of thyroid tumours characterised by different aggressiveness showed that the expression of OIS markers such as p16 INK4a, p21 CIP1 and IGFBP7 is upregulated at early stages, and lost during thyroid tumour progression. Taken together, our results suggest a role of OIS in thyroid carcinogenesis.

show abstract

“…The p16-targeting siRNA sequences were as follows: 5 0 -GAGGAGGTGCGGGCGCT GC-3 0 (Voorhoeve and Agami, 2003), termed clone 1 (p16#1), and 5 0 -CGCACCGAATAGTTACGGT-3 0 (Bond et al, 2004), termed clone 2 (p16#2), respectively.…”

Section: Rna Interferencementioning

confidence: 99%

p300 plays a role in p16INK4a expression and cell cycle arrest

et al. 2007

View full text Add to dashboard Cite

As a cyclin-dependent kinase inhibitor, p16 INK4a plays a key role in cell cycle progression and cellular differentiation, and its expression is frequently altered in human cancers through epigenetically mediated transcriptional silencing. In this report, we demonstrate that p300 was able to induce cell cycle arrest, and this process was reversed by p16 INK4a silencing by RNA interference in HeLa cells. We also show that p300 was involved in activation of p16 INK4a expression in 293T cells. Specifically, p300 cooperated with Sp1 to stimulate both p16 INK4a promoter activity and mRNA expression. Co-immunoprecipitation and mammalian twohybrid assays revealed that p300 and Sp1 formed a complex through interaction between the Q domain of p300 and the N-terminal domain of Sp1. The chromatin immunoprecipitation assays verified that p300 was recruited to p16 INK4a promoter, and the histone acetyltransferase domain of p300 participated in p16 INK4a activation through inducing hyperacetylation of histone H4 at p16 INK4a gene. These data suggest that p300 plays a critical role in transcriptional regulation of p16 INK4a and in cell cycle arrest.

show abstract

Direct evidence from siRNA-directed “knock down” that p16INK4a is required for human fibroblast senescence and for limiting ras-induced epithelial cell proliferation

Cited by 44 publications

References 16 publications

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

Expression of hTERT immortalises normal human urothelial cells without inactivation of the p16/Rb pathway

Evidence of oncogene-induced senescence in thyroid carcinogenesis

p300 plays a role in p16INK4a expression and cell cycle arrest

Contact Info

Product

Resources

About