Bmi-1 Reduction Plays a Key Role in Physiological and Premature Aging of Primary Human Keratinocytes

Cordisco, Sonia; Maurelli, Riccardo; Bondanza, Sergio; Stefanini, Miria; Zambruno, Giovanna; Guerra, Liliana; Dellambra, Elena

doi:10.1038/jid.2009.355

Cited by 61 publications

(94 citation statements)

References 42 publications

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“…It is highly expressed in holoclones and appears down-regulated already in holoclones with lower clonogenic potential, suggesting that Bmi-1 levels are crucial for p16 expression during clonal conversion. 8 What is more, inactivation of p16 INK4a in human epidermal SCs is necessary for maintaining their stemness and this process might be regulated by Bmi-1 expression. 7 Bmi-1 modulates p16 INK4a levels and delays clonal conversion even in primary keratinocytes from elderly donors and from young patients suffering from premature aged syndromes.…”

Section: -9 P16mentioning

confidence: 99%

“…7 Bmi-1 modulates p16 INK4a levels and delays clonal conversion even in primary keratinocytes from elderly donors and from young patients suffering from premature aged syndromes. 8 In addition, Cbx4, a PRC1 associated protein, maintains SCs in an undifferentiated state by regulating Polycomb Group (PcG) proteins (Ezh2, Dnmt1 and Bmi-1) and preventing the active SC state. 12 Of note, genetic and epigenetic mechanisms determine p16 loss and Bmi-1 overexpression in skin tumors.…”

Section: -9 P16mentioning

confidence: 99%

“…4,7,11 It is undetectable in holoclones and well-expressed in meroclones and paraclones. 8 Bmi-1 is a component of Polycomb Repressive Complex 1 (PRC1) that regulate the balance of SC dormancy and activation by modifying chromatin and suppressing gene expression. It is highly expressed in holoclones and appears down-regulated already in holoclones with lower clonogenic potential, suggesting that Bmi-1 levels are crucial for p16 expression during clonal conversion.…”

Section: -9 P16mentioning

confidence: 99%

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Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

Dellambra¹

2016

Small GTPases

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The human epidermal clonal evolution, i.e. the transition from stem cells (SCs) to transient amplifying (TA)-cells and post-mitotic cells, is a continuous and tightly regulated process that ensures physiologic tissue homeostasis. The Ras family of small GTPases has a key role in skin homeostasis and tumorigenesis. Indeed, activating mutations in Ras genes have been found in human cutaneous squamous cell carcinomas (cSCCs) and in experimentally-induced murine cSCCs. In mouse models, the Ras signaling might lead to hyperproliferative phenotypes, including the development of cSCCs, depending on the nature of the founding cells. Tumor-initiating cells or Cancer Stem Cells (CSCs) have been demonstrated in murine and human cSCCs even if the mechanism of their development from normal SCs or TA-cells is not completely elucidated. Here, the relation between the Ras expression outcome and the clonogenic potential of the target keratinocyte is discussed.

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Section: -9 P16mentioning

confidence: 99%

Section: -9 P16mentioning

confidence: 99%

Section: -9 P16mentioning

confidence: 99%

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Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

Dellambra¹

2016

Small GTPases

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“…The activation of the Ink4a/Arf/Ink4b locus is a hallmark of aging ), and indeed expression of PRC subunits is often reduced in aged skin (Ressler et al 2006;Cordisco et al 2010). However, the specifics of how this activation leads to the familiar phenotypes associated with aging are unclear.…”

Section: Regulation Of the Repressive H3k27me3 Histone Markmentioning

confidence: 99%

Epigenetic Regulation of Epidermal Differentiation

Perdigoto

Valdés

Bardot

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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In a cell, the chromatin state is controlled by the highly regulated interplay of epigenetic mechanisms ranging from DNA methylation and incorporation of different histone variants to posttranslational modification of histones and ATP-dependent chromatin remodeling. These changes alter the structure of the chromatin to either facilitate or restrict the access of transcription machinery to DNA. These epigenetic modifications function to exquisitely orchestrate the expression of different genes, and together constitute the epigenome of a cell. In the skin, different epigenetic regulators form a regulatory network that operates to guarantee skin stem cell maintenance while controlling differentiation to multiple skin structures. In this review, we will discuss recent findings on epigenetic mechanisms of skin control and their relationship to skin pathologies.

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“…Senescence may be induced by multiple cellular stress stimuli, including oncogene activation, overproduction of reactive oxygen species, or simply by the end of proliferative potential, that is, replicative senescence (3)(4)(5)(6). In tissues with high turnover, such as the epidermis, replicative senescence plays a crucial role in the time-dependent changes occurring in the tissue (7). When normal cells enter a state of replicative senescence, they block progression from the G1 to the S phase by maintaining the retinoblastoma (Rb) protein in a hypophosphorylated state (8,9).…”

mentioning

confidence: 99%

p63-microRNA feedback in keratinocyte senescence

Melino

Saintigny²,

Mahé³

et al. 2013

Annales de Dermatologie et de Vénéréologie

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We investigated the expression of microRNAs (miRNAs) associated with replicative senescence in human primary keratinocytes. A cohort of miRNAs up-regulated in senescence was identified by genome-wide miRNA profiling, and their change in expression was validated in proliferative versus senescent cells. Among these, miRNA (miR)-138, -181a, -181b, and -130b expression increased with serial passages. miR-138, -181a, and -181b, but not miR130b, overexpression in proliferating cells was sufficient per se to induce senescence, as evaluated by inhibition of BrdU incorporation and quantification of senescence-activated β-galactosidase staining. We identified Sirt1 as a direct target of miR-138, -181a, and -181b, whereas ΔNp63 expression was inhibited by miR-130b. We also found that ΔNp63α inhibits miR-138, -181a, -181b, and -130b expression by binding directly to p63-responsive elements located in close proximity to the genomic loci of these miRNAs in primary keratinocytes. These findings suggest that changes in miRNA expression, by modulating the levels of regulatory proteins such as p63 and Sirt1, strongly contribute to induction of senescence in primary human keratinocytes, thus linking these two proteins. Our data also indicate that suppression of miR-138, -181a, -181b, and -130b expression is part of a growth-promoting strategy of ΔNp63α in epidermal proliferating cells.

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Bmi-1 Reduction Plays a Key Role in Physiological and Premature Aging of Primary Human Keratinocytes

Cited by 61 publications

References 42 publications

Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

Oncogenic Ras: A double-edged sword for human epidermal stem and transient amplifying cells

Epigenetic Regulation of Epidermal Differentiation

p63-microRNA feedback in keratinocyte senescence

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