Michaloglou C, Vredeveld LCW, Soengas MS, Denoyelle C, Kuilman T, van der Horst CMAM et al.. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436: 720-724

Division of Molecular Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Nature (Impact Factor: 41.46). 09/2005; 436(7051):720-4. DOI: 10.1038/nature03890
Source: PubMed


Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes; however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF, a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma). This raises the question of whether naevi undergo BRAF(V600E)-induced senescence. Here we show that sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)-driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.

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Available from: Chantal M A M van der Horst
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    • "However, the length of time within the tissue is clearly a major factor in determining whether the effect of entry into senescence will be beneficial or deleterious to the organism. The appearance of senescent cells in the short-term probably facilitates important physiological functions such as tumour suppression (Braig et al. 2005, Chen et al. 2005, Michaloglou et al. 2005, Collado et al. 2005), wound healing (Krizhanovsky et al. 2008, Jun et al. 2010, Fitzner et al. 2012, Kim et al. 2013, Demaria et al. 2014) and possibly placental development (Chuprin et al. 2013, Rajagopalan and Long, 2012, Zhang et al. 2014). However, senescent cells are known to accumulate in vivo, possibly as a result of impaired immune clearance by an ageing immune system (Burton, 2009). "
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    ABSTRACT: Cellular senescence was first reported in human fibroblasts as a state of stable in vitro growth arrest following extended culture. Since that initial observation, a variety of other phenotypic characteristics have been shown to co-associate with irreversible cell cycle exit in senescent fibroblasts. These include (1) a pro-inflammatory secretory response, (2) the up-regulation of immune ligands, (3) altered responses to apoptotic stimuli and (4) promiscuous gene expression (stochastic activation of genes possibly as a result of chromatin remodeling). Many features associated with senescent fibroblasts appear to promote conversion to an immunogenic phenotype that facilitates self-elimination by the immune system. Pro-inflammatory cytokines can attract and activate immune cells, the presentation of membrane bound immune ligands allows for specific recognition and promiscuous gene expression may function to generate an array of tissue restricted proteins that could subsequently be processed into peptides for presentation via MHC molecules. However, the phenotypes of senescent cells from different tissues and species are often assumed to be broadly similar to those seen in senescent human fibroblasts, but the data show a more complex picture in which the growth arrest mechanism, tissue of origin and species can all radically modulate this basic pattern. Furthermore, well-established triggers of cell senescence are often associated with a DNA damage response (DDR), but this may not be a universal feature of senescent cells. As such, we discuss the role of DNA damage in regulating an immunogenic response in senescent cells, in addition to discussing less established “atypical” senescent states that may occur independent of DNA damage.
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    • "kely the consequence of abnormal RAS activity and was already described in human fibroblasts or in NF1 - derived benign tumors such as neurofibromas or astrocytomas ( Courtois - Cox et al . , 2006 ; Jacob et al . , 2011 ) . In a similar manner , melanocytes in human nevi show several senescence markers due to the presence of oncogenic BRAF V600E ( Michaloglou et al . , 2005 ) . Noticeably , our list of differen - tially expressed genes also contained 26 upregulated SASP markers in NF1 + / À iPSCs ( Table S4 ) . Only CCL2 and CXCL12 were overlapping with the Bio - Plex assay results , and the remaining SASP markers were mainly restricted to genes belonging to the collagen and laminin families , to the IGFBP"
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is a frequent genetic disease leading to the development of Schwann cell-derived neurofibromas or melanocytic lesions called café-au-lait macules (CALMs). The molecular mechanisms involved in CALMs formation remain largely unknown. In this report, we show for the first time pathophysiological mechanisms of abnormal melanocyte differentiation in a human NF1(+/-) induced pluripotent stem cell (iPSC)-based model. We demonstrate that NF1 patient-derived fibroblasts can be successfully reprogrammed in NF1(+/-) iPSCs with active RAS signaling and that NF1 loss induces senescence during melanocyte differentiation as well as in patient's-derived CALMs, revealing a new role for NF1 in the melanocyte lineage. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
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    • "A replicative mode of cellular senescence can be triggered by the following two kinds of intrinsic stresses that are coupled to cell division: (1) the gradual loss of telomeric DNA elements at S phases of successive mitotic cell divisions leading to telomeric dysfunction and causing a form of cellular senescence known as telomere-initiated senescence; and (2) the steady rise in the expression of the INK4a/ARF locus leading to a progressing with the proliferative history of cells accumulation of the p16INK4a and p14ARF tumor suppressor proteins [1, 11- 13, 22, 86-89, 91]. Some stresses can trigger a mode of cellular senescence known as premature or stress-induced senescence; these stresses include: (1) an accumulation of unrepaired damage to chromosomal DNA and the resulting genomic damage at non-telomeric sites; (2) chromatin remodeling resulting in heterochromatin foci formation and large-scale chromatin condensation; (3) oncogene overexpression/ activation or tumor suppressor gene inactivation, all causing a so-called oncogeneinduced form of cellular senescence; (4) an enhanced expression of cell proliferation activators that create robust mitogenic signals; (5) an excessive proliferation of dysfunctional mitochondria, which results in ROS accumulation and oxidative stress; (6) autophagy induction; and (7) changes in expression patterns of numerous microRNAs [3] [4] [7] [12] [22] [23] [86] [97] [98] [99] [100] [101] [102] [103] [104] [105] [106] [107] [108] [109] [110] [111] [112] [113] [114] [115] [116]. "
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    ABSTRACT: Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research.
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