Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice

Krimpenfort, Paul; Quon, Kim; Mooi, Wolter J.; Loonstra, Ate; Berns, Anton

doi:10.1038/35092584

Cited by 505 publications

(408 citation statements)

References 25 publications

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“…Other strong indicators for a favorable prognosis in our study include tumor diameter o4 cm, low/no expression of cyclin D1, and low/no tobacco consumption. In accordance with most other studies on HPV-related oropharyngeal carcinomas, we also found a favorable disease-specific survival in patients with HPV16-positive tonsillar squamous cell carcinomas, 12,46,[60][61][62][63][64] and p14 ARF overexpression, 31 although with less significance than the indicators described above. We noticed that lymph node status, which is generally considered as the most important prognostic factor in head-and-neck squamous cell carcinomas, 23 had little value in our series of tonsillar squamous cell carcinomas, which is in concordance with other studies.…”

Section: Discussionsupporting

confidence: 92%

“…In the HPV-negative tumors both p14 ARF as well as p16 INK4A were often undetectable, which is in accordance with the fact that their expression is downregulated in most headand-neck squamous cell carcinomas due to gene inactivation at the 9p21 locus. 45,46 In normal tissue cells, p14 ARF upregulation might lead to p53 upregulation, but in HPV-positive tonsillar squamous cell carcinomas, this is usually counteracted by means of functional inactivation of wild-type p53 by the viral E6 protein. In contrast and as observed in our study, p53 is frequently upregulated in HPVnegative tumors due to mutations in the TP53 gene as a result of exposure to tobacco and/or alcohol.…”

Section: Discussionmentioning

confidence: 99%

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P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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Human papillomavirus is involved in the carcinogenesis of tonsillar squamous cell carcinomas. Here, we investigated the expression and the prognostic value of key cell cycle proteins in the pRb and p53 pathways in both human papillomavirus type 16-positive and -negative tonsillar squamous cell carcinomas. Using immunohistochemistry, 77 tonsillar squamous cell carcinomas with known human papillomavirus type 16 status and clinical outcome were analyzed for expression of Ki67, p16 INK4A, cyclin D1, pRb, p14 ARF , MDM2, p53, p21 Cip1/WAF1 , and p27 KIP1 . Results were correlated with each other and with clinical and demographic patient data. A total of 35% of tonsillar carcinomas harbored integrated human papillomavirus type 16 DNA and p16 INK4A overexpression, both being considered essential features for human papillomavirus association. These tumors also showed the overexpression of p14 ARF (Po0.0001) and p21 Cip1/WAF1 (P ¼ 0.001), and downregulation of pRb (Po0.0001) and cyclin D1 (P ¼ 0.027) compared with the human papillomavirus-negative cases. Univariate Cox regression analyses revealed a favorable survival rate for non-smokers (P ¼ 0.006), as well as for patients with T1-2 tumors (Po0.0001) or tumors showing low expression of cyclin D1 (P ¼ 0.028), presence of human papillomavirus and overexpression of p16 INK4A (P ¼ 0.01), p14 ARF (P ¼ 0.02) or p21 Cip1/WAF1 (P ¼ 0.004). In multivariate regression analyses, smoking and tumor size, as well as expression of cyclin D1 and p21 Cip1/WAF1 , were found to be independent prognostic markers. We conclude that human papillomavirus positivity in tonsillar squamous cell carcinomas strongly correlates with p21 Cip1/WAF1 and p14 ARF overexpression and downregulation of pRb and cyclin D1. In particular p21 Cip1/WAF1 overexpression is an excellent favorable prognosticator in tonsillar squamous cell carcinomas. Modern Pathology ( Head-and-neck squamous cell carcinoma is the sixth most prevalent malignancy in the world, contributing 6% of new cancer cases annually worldwide. 1,2 These tumors have a 5-year survival rate of approximately 50%, which has not improved in the last two decades. 3 Well-recognized risk factors in the etiology of head-and-neck squamous cell carcinomas are extensive tobacco and alcohol consumption in B90% of cases, as well as oncogenic human papillomaviruses (HPVs), predominantly HPV type 16. 3,4 Interestingly, the association of HPV is strongest for tonsillar squamous cell carcinoma with a prevalence up to 50%. [5][6][7][8]

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

et al. 2009

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“…The p53 flox/flox (Marino et al, 2000) and p16 ink4aÀ/À (Krimpenfort et al, 2001) mice were kindly provided by A Berns. All mice used for this analysis were predominantly on a FVB/N mixed strain, with Figure 7 Proposed model of meningioma initiation in the mesoderm-and neural crest-derived meningeal lineages.…”

Section: Micementioning

confidence: 99%

Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes

et al. 2011

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Meningiomas are among the most common primary central nervous system tumours in adults. Studies focused on the molecular basis for meningioma development are hampered by a lack of information with regard to the cell of origin for these brain tumours. Herein, we identify a prostaglandin D synthase-positive meningeal precursor as the cell of origin for murine meningioma, and show that neurofibromatosis type 2 (Nf2) inactivation in prostaglandin D2 synthase (PGDS) ( þ ) primordial meningeal cells, before the formation of the three meningeal layers, accounts for the heterogeneity of meningioma histological subtypes. Using a unique PGDSCre strain, we define a critical embryonic and early postnatal developmental window in which biallelic Nf2 inactivation in PGDS ( þ ) progenitor cells results in meningioma formation. Moreover, we identify differentially expressed markers that characterize the two major histological meningioma subtypes both in human and mouse tumours. Collectively, these findings establish the cell of origin for these common brain tumours as well as a susceptible developmental period in which signature genetic mutations culminate in meningioma formation.

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“…9 In fact, many of the melanoma-associated tumor suppressor genes identified to date are themselves involved in control of senescence, including BRAF (encoding serine/threonine-protein kinase B-raf), CKD4 (cyclin-dependent kinase 4), and CDKN2A (encoding cyclin-dependent kinase inhibitor 2A isoforms p16 INK4a and p19 ARF ). 3,10 Nevi frequently harbor oncogenic mutations of the tyrosine kinase BRAF gene, particularly V600E, 11 and BRAF V600E is also found in approximately 70% of cutaneous melanomas. 12 Expression of BRAF V600E in human melanocytes leads to oncogene-induced senescence, 8 which can be considered as a mechanism that protects from malignant progression.…”

mentioning

confidence: 99%

Pirin Inhibits Cellular Senescence in Melanocytic Cells

Licciulli

Luise

Scafetta

et al. 2011

The American Journal of Pathology

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Cellular senescence has been widely recognized as a tumor suppressing mechanism that acts as a barrier to cancer development after oncogenic stimuli. A prominent in vivo model of the senescence barrier is represented by nevi, which are composed of melanocytes that, after an initial phase of proliferation induced by activated oncogenes (most commonly BRAF), are blocked in a state of cellular senescence. Transformation to melanoma occurs when genes involved in controlling senescence are mutated or silenced and cells reacquire the capacity to proliferate. Pirin (PIR) is a highly conserved nuclear protein that likely functions as a transcriptional regulator whose expression levels are altered in different types of tumors. We analyzed the expression pattern of PIR in adult human tissues and found that it is expressed in melanocytes and has a complex pattern of regulation in nevi and melanoma: it is rarely detected in mature nevi, but is expressed at high levels in a subset of melanomas. Loss of function and overexpression experiments in normal and transformed melanocytic cells revealed that PIR is involved in the negative control of cellular senescence and that its expression is necessary to overcome the senescence barrier. Our results suggest that PIR may have a relevant role in melanoma progression.

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Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice

Cited by 505 publications

References 25 publications

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

P21Cip1/WAF1 expression is strongly associated with HPV-positive tonsillar carcinoma and a favorable prognosis

Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes

Pirin Inhibits Cellular Senescence in Melanocytic Cells

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