The human melanocyte: a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells

Bandyopadhyay, Debdutta; Timchenko, Nikolai A.; Suwa, Tetsuya; Hornsby, Peter J.; Campisi, Judith; Medrano, Estela E.

doi:10.1016/s0531-5565(01)00098-5

Cited by 68 publications

(65 citation statements)

References 35 publications

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“…Results were somewhat variable but it was concluded that p16 levels rose in both cases, with dephosphorylation of RB1 where tested, whereas levels of the p53-activated inhibitor p21 rose significantly only in the cells senescing without cAMP agonists (Haddad et al, 1998;Bandyopadhyay et al, 2001). Accumulation of another CDK inhibitor p27 was observed in the presence of cAMP agonists (Haddad et al, 1998).…”

Section: Senescence In Cultured Human Melanocytesmentioning

confidence: 99%

“…CT is one of a set of supplements that increase cellular cAMP signaling; others include melanocyte-stimulating hormone (MSH), theophylline, dibutyryl cAMP and isobutyl methylxanthine (IBMX). Comparisons between the two specific media led to the conclusion that lifespans of neonatal human melanocytes were shorter in a medium containing CT and IBMX (13-15 pd) than in the same basic medium without cAMP agonists but containing TPA (40-60 pd) (Medrano et al, 1994;Bandyopadhyay et al, 2001). The cAMP agonists appeared more important than the TPA in producing this difference, since neonatal melanocytes grown with TPA as well as CT and dibutyryl cAMP were reported to grow for only about 12 pd (Halaban et al, 2000).…”

Section: Senescence In Cultured Human Melanocytesmentioning

confidence: 99%

“…However, the latter authors did not test their cells for chromosomal aberrations, nor for spontaneous telomerase activation, so it is possible that the immortalization was associated with additional spontaneous genetic change. Bandyopadhyay et al (2001) reported a major extension of lifespan of normal melanocytes (grown with cAMP agonists) using hTERT alone. This too seems surprising since the p16/RB pathway was not manipulated; however, the hTERT-treated cells showed a number of changes in protein expression including reduced levels of p16 (Bandyopadhyay et al, 2001).…”

Section: Genetic Analysis Of Human Melanocyte Senescence and Immortalmentioning

confidence: 99%

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Human melanocyte senescence and melanoma susceptibility genes

2003

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The molecular mechanisms and biology of cellular senescence in human melanocytes are discussed, including similarities to and differences from senescence in fibroblasts and other cell lineages. Special reference is made to the fact that the known melanoma susceptibility genes in the human, Inhibitor A of [cyclin-dependent] kinase 4-alternative reading frame (INK4A-ARF) and cyclindependent kinase 4, are involved in the regulation of cellular senescence, and possible reasons why this should be so. Based on the evidence including growth and survival kinetics of human and mouse melanocytes carrying germline deficiencies in the INK4A sequence, it is suggested that an 'M0' or p16/RB-dependent form of senescence may be particularly important in melanocytes. A speculative model is proposed, relating current concepts of early melanoma progression to the processes of cellular senescence and immortalization. This includes the suggestion that moles or nevi are senescent clones of melanocytes.

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Section: Senescence In Cultured Human Melanocytesmentioning

confidence: 99%

Section: Senescence In Cultured Human Melanocytesmentioning

confidence: 99%

Section: Genetic Analysis Of Human Melanocyte Senescence and Immortalmentioning

confidence: 99%

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Human melanocyte senescence and melanoma susceptibility genes

2003

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“…Moreover, immunoblot analysis ( Figure 1C) revealed virtually no p16 in either of the two cultures that immortalised with hTERT alone. p16 is normally expressed by high-passage human melanocytes (Bandyopadhyay et al, 2001;Bennett and Medrano, 2002) Higher magnification (bottom) shows some acidic b-galactosidase reactivity in whole basal epidermis (arrowheads), but faint compared to naevus cells. Note: frozen sections were needed for this stain, and were available only for congenital naevi.…”

Section: Immortalisation Of Normal Human Melanocytesmentioning

confidence: 99%

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

et al. 2006

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Cellular senescence, the irreversible proliferative arrest seen in somatic cells after a limited number of divisions, is considered a crucial barrier to cancer, but direct evidence for this in vivo was lacking until recently. The best-known form of human cell senescence is attributed to telomere shortening and a DNA-damage response through p53 and p21. There is also a more rapid form of senescence, dependent on the p16-retinoblastoma pathway. p16 (CDKN2A) is a known melanoma susceptibility gene. Here, we use retrovirally mediated gene transfer to confirm that the normal form of senescence in cultured human melanocytes involves p16, since disruption of the p16/retinoblastoma pathway is required as well as telomerase activation for immortalisation. Expression (immunostaining) patterns of senescence mediators and markers in melanocytic lesions provide strong evidence that cell senescence occurs in benign melanocytic naevi (moles) in vivo and does not involve p53 or p21 upregulation, although p16 is widely expressed. In comparison, dysplastic naevi and early (radial growth-phase, RGP) melanomas show less p16 and some p53 and p21 immunostaining. All RGP melanomas expressed p21, suggesting areas of p53-mediated senescence, while most areas of advanced (vertical growthphase) melanomas lacked both p16 and p21, implying escape from both forms of senescence (immortalisation). Moreover, nuclear p16 but not p21 expression can be induced in human melanocytes by oncogenic BRAF, as found in around 80% of naevi. We conclude that cell senescence can form a barrier to melanoma development. This also provides a potential explanation of why p16 is a melanoma suppressor gene.

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“…Premature senescence can be triggered by many stimuli, including oncogene imbalance. Like replicative senescence, oncogene-induced premature senescence is identified by senescence biomarkers such as senescenceassociated b-galactosidase (SA-b-gal) (Dimri et al, 1995), and is accompanied by increased expression of negative growth regulators including p53, p21 WAF1 and p16 INK4A (Bandyopadhyay et al, 2001;Bennett, 2003;Ohtani et al, 2004;Takahashi et al, 2006;Haferkamp et al, 2008). Several recent studies have shown that oncogene-induced premature senescence indeed occurs in premalignant human tumors and provides an initial barrier to tumor genesis in vivo (Hornsby, 2007;Acosta et al, 2008;Ansieau et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Wang

Liu

et al. 2010

Oncogene

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Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras-and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16 INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16 INK4A gene contains an HBP1-binding site at position À426 to À433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16 INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16 INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16 INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

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The human melanocyte: a model system to study the complexity of cellular aging and transformation in non-fibroblastic cells

Cited by 68 publications

References 35 publications

Human melanocyte senescence and melanoma susceptibility genes

Human melanocyte senescence and melanoma susceptibility genes

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

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

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