Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

Gray-Schopfer, Vanessa C.; Cheong, Sok Ching; Chong, Heung; Chow, J. W. M.; Moss, Tony; Abdel‐Malek, Zalfa; Marais, Richard; Wynford-Thomas, David; Bennett, Dorothy C.

doi:10.1038/sj.bjc.6603283

Cited by 359 publications

(378 citation statements)

References 51 publications

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“…A mutation in a downstream effector of Ras, BRAF (BRAFv600E), is often found in these tumors. BRAFv600E expression in human melanocytes induces cell cycle arrest, accompanied by p16 Ink4a overexpression and senescence-associated acidic b-galactosidase activity (Michaloglou et al, 2005;Gray-Schopfer et al, 2006). Recent evidence has described a similar situation in schwannomas and neurofibromas (Romagosa et al, 2009).…”

Section: Subcellular Location Of P16 Ink4a Overexpressionmentioning

confidence: 91%

“…Supporting this concept, senescent cells have been shown in a number of different benign lesions, including nevi and neurofibromas (Michaloglou et al, 2005;Courtois-Cox et al, 2006), but not in malignant lesions. p16 Ink4a overexpression has been found in premature senescence, and particularly in OIS, and consequently in benign and premalignant lesions with senescent cells (Krishnamurthy et al, 2004;Michaloglou et al, 2005;Gray-Schopfer et al, 2006). Human nevi are benign proliferations of melanocytes, and represent the paradigm of OIS in human tumors.…”

Section: Subcellular Location Of P16 Ink4a Overexpressionmentioning

confidence: 99%

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p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

et al. 2011

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p16 Ink4a is a protein involved in regulation of the cell cycle. Currently, p16 Ink4a is considered a tumor suppressor protein because of its physiological role and downregulated expression in a large number of tumors. Intriguingly, overexpression of p16 Ink4a has also been described in several tumors. This review attempts to elucidate when and why p16 Ink4a overexpression occurs, and to suggest possible implications of p16 Ink4a in the diagnosis, prognosis and treatment of cancer.

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Section: Subcellular Location Of P16 Ink4a Overexpressionmentioning

confidence: 91%

Section: Subcellular Location Of P16 Ink4a Overexpressionmentioning

confidence: 99%

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

et al. 2011

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“…[4] Bu paradoks (melanositik nevüslerde olan BRAF V600E mutantının melanomaya ilerlememesi) 2006'da tümör supresör p16 ve beta galaktozidaz belirtecinin yüksek olmasına ba¤lanmıtır. [5,6] BRAF V600E'nin aırı ekspresyonu primer insan melanositlerinde hücre ço¤almasını bozmaktadır. [6] Spitz nevüslerde (melanoma ile karıabilmekte) ise MAPK aktivitesi fazla, fakat hücre ço¤alması düüktür.…”

Section: Tartimaunclassified

“…[5,6] BRAF V600E'nin aırı ekspresyonu primer insan melanositlerinde hücre ço¤almasını bozmaktadır. [6] Spitz nevüslerde (melanoma ile karıabilmekte) ise MAPK aktivitesi fazla, fakat hücre ço¤alması düüktür. [7] Bir çalımada erüptif melanositik nevüs takibi yapılan ve 6-merkaptopürin kullanılan hastaların ekil 1.…”

Section: Tartimaunclassified

A case of eruptive melanocytic naevi after long-term azathioprine treatment

Eken¹

2016

FNG & Bilim Tıp Dergisi

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“…They further demonstrate that, despite the cytostatic nature of the senescence program, senescent cells can turn over in vivo. Whether such turnover is a general feature of senescence in vivo is not clear 14,28 , but when present may reinforce the tumour suppressive action of senescence in pre-malignant settings or in tumours following treatment with senescence-or differentiation-promoting therapies 26,29 . Conversely, our results identify a setting in which the innate immune system is provoked to coordinately attack tumour cells, presumably through both phagocytosis and direct cytotoxic killing, thereby facilitating their elimination.…”

mentioning

confidence: 99%

Erratum: Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Xue¹,

Zender²,

Miething³

et al. 2011

Nature

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Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence 1,2 . Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies 3 . To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma 4,5 . We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.p53 mutations are common in human liver cancer 6 , which is typically highly aggressive and resistant to non-surgical therapies. To determine the requirement for p53 loss in the maintenance of such carcinomas, we used reversible RNAi 7 to control p53 in a chimaeric liver cancer mouse model (Fig. 1a) 4,5 . Purified embryonic liver progenitor cells (hepatoblasts) were transduced with retroviruses expressing oncogenic ras (HrasV12), the tetracycline transactivator protein tTA ('tet-off') and a tet-responsive p53 miR30 design short hairpin RNA (shRNA; Supplementary Fig. 1a) 7,8 , and seeded into the livers of athymic nude mice following intrasplenic injection 4,5 . To facilitate in vivo imaging, the oncogenic ras retrovirus co-expressed green fluorescent protein (GFP) and, in some experiments, hepatoblasts were also co-transduced with a luciferase reporter.p53 expression was efficiently suppressed in the absence of doxycycline (Dox) and rapidly restored following Dox addition ( Supplementary Fig. 1b, c). On transplantation into the livers of recipient mice, hepatoblast populations co-expressing Ras and the conditional p53 shRNA rapidly produced invasive hepatocarcinomas in the absence of Dox (Fig. 1b), whereas cells expressing each vector alone did not (data not shown). These tumours were GFP-positive and, if expressing luciferase, could be visualized externally by bioluminescence imaging (Fig. 1b).

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Cellular senescence in naevi and immortalisation in melanoma: a role for p16?

Cited by 359 publications

References 51 publications

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors

A case of eruptive melanocytic naevi after long-term azathioprine treatment

Erratum: Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

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