p16<sup>INK4A</sup> is a robust <i>in vivo</i> biomarker of cellular aging in human skin

Ressler, Sigrun; Bártková, Jiřina; Niederegger, Harald; Bártek, Jiří; Scharffetter‐­Kochanek, Karin; Jansen‐Dürr, Pidder; Wlaschek, Meinhard

doi:10.1111/j.1474-9726.2006.00231.x

Cited by 500 publications

(411 citation statements)

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“…Expression of p16 Ink4a markedly increases with ageing in most mouse tissues and in human skin and kidney tissues (Zindy et al, 1997;Ressler et al, 2006), suggesting the importance of this tumor suppressor in ageing and senescence (Hara et al, 1996;Zhu et al, 2002). In addition, p16 Ink4a overexpression has been reported in senescent fibroblasts , in response to oxidative stress (Ksiazek et al, 2006;Quereda et al, 2007), DNA damage and changes in chromatin structure (Canepa et al, 2007;Fordyce et al, 2010).…”

Section: Physiological Role Of P16 Ink4amentioning

confidence: 99%

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: Physiological Role Of P16 Ink4amentioning

confidence: 99%

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

et al. 2011

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“…The presence of cells in vivo, which closely resemble the phenotype of senescent cells replicatively aged in culture, has been observed in human skin (Dimri et al, 1995;Ressler et al, 2006) as well as in the vascular system (Vasile et al, 2001). It is thus conceivable that also stem cells reach an equivalent state of senescence in vivo, but the proof of this hypothesis is still missing.…”

Section: Msc In Vitro Senescencementioning

confidence: 99%

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

Lepperdinger

Brunauer

Jamnig

et al. 2008

Experimental Gerontology

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“…However, p14 ARF /p16 INK4a expression was also described to be a biomarker of age in rodents and in human skin. 23,24 The influence of age in p16-based cervical cancer screening has not been described yet, and may help to improve data interpretation.…”

Section: Discussionmentioning

confidence: 99%

“…24 Their physiological function is the control of the state of cellular replicative senescence. Such upregulation in older patients may interfere with the high-risk HPV-related upregulation of p14 ARF and p16 INK4A in cervical intraepithelial neoplasia.…”

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confidence: 99%

p16INK4a and p14ARF mRNA expression in Pap smears is age-related

et al. 2012

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Expression of high-risk HPV oncogenes results in a strong overexpression of cellular protein p16 INK4a . Immunohistochemical staining for p16 INK4a is widely used as diagnostic marker. However, p16 INK4a upregulation was also described as a biomarker of age. Here we analyzed p16 INK4a expression in cervical smears to investigate if patient age may influence p16 INK4a -based cervical cancer diagnosis. p14 ARF was analyzed as a related supportive biomarker. Cervical scrapes were taken and stored in RNAlater. Total RNA was extracted, and cDNA was analyzed for expression of p16 INK4a and p14 ARF relative to b-actin, by real-time reverse transcriptase PCR SYBR-Green I assays. Patient-derived smears referred as HSIL (n ¼ 45) had 6.27-fold higher p16 INK4a mRNA expression than smears of cytologically normal and HPV-negative persons (n ¼ 48). Expression of p14 ARF was 4.87-fold higher. When women with normal diagnoses were stratified for age, a significantly enhanced p16 INK4a (2.88-fold) and p14 ARF (1.9-fold) expression was observed as a consequence of ageing. A significant age-dependent upregulation was also observed in older HSIL patients (2.54-fold). Our study revealed significantly enhanced expression of p16 INK4a /p14 ARF mRNA in cervical scrapes referred to as HSIL compared with normal women. An age-dependent bias has to be considered when quantifying these tumor suppressor genes, with respect to cervical cancer development. Modern Pathology (2012) 25, 465-470; doi:10.1038/modpathol.2011.179; published online 11 November 2011Keywords: biomarker; cervical cancer; CDKN2A; cytology Cervical cancer is the second leading cause of cancer deaths for women worldwide. 1 Today, cervical cancer screening programs mostly rely on cytology. The Pap-test introduced more than 60 years ago by Papanicolaou 2 remarkably reduced the mortality by cervical cancer. 3 Pap screening has high specificity for disease, but suffers from suboptimal sensitivity and observer subjectivity that is partially compensated by frequent testing. 4 Therefore, supportive molecular alternative methods are highly desirable.Human papillomavirus is a necessary cause of invasive cervical cancer. 5 Therefore, HPV testing is being discussed as a primary screening method, for triaging of equivocal results, and follow-up after therapeutic intervention. 6 High-risk HPV infections are not sufficient for the development of cervical cancer. Most individuals remain asymptomatic and clear HPV infections spontaneously within approximately 8-10 months. 7 The immortalization of primary human keratinocytes can be sufficiently maintained by the expression of the high-risk HPV E6 and E7 oncogenes. These oncogenes are required for initiation and all subsequent stages of carcinogenic progression. 8 The focus on HPV oncogene mRNA expression could be a promising strategy to identify transformation events, but requires multiplex approaches to deal with HPV type-specific transcripts. The proteins p16 INK4a (CDKN2A) and p14 ARF (CDKN2B) are generally upregulated in transformed ce...

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p16^INK4A is a robust in vivo biomarker of cellular aging in human skin

Abstract: SummaryThe cell-cycle regulating gene, p16 INK4A, encoding an inhibitor of cyclin-dependent kinases 4 and 6, is considered to play an important role in cellular aging and in premature senescence.

Cited by 500 publications

References 50 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

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

p16INK4a and p14ARF mRNA expression in Pap smears is age-related

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p16INK4A is a robust in vivo biomarker of cellular aging in human skin

Abstract: SummaryThe cell-cycle regulating gene, p16 INK4A, encoding an inhibitor of cyclin-dependent kinases 4 and 6, is considered to play an important role in cellular aging and in premature senescence.

Cited by 500 publications

References 50 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

Controversial issue: Is it safe to employ mesenchymal stem cells in cell-based therapies?

p16INK4a and p14ARF mRNA expression in Pap smears is age-related

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p16^INK4A is a robust in vivo biomarker of cellular aging in human skin