BRAFE600-associated senescence-like cell cycle arrest of human naevi
Open accessAbstract
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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In mice and humans, a senescence response to strong mitogenic signals prevents premalignant lesions from progressing to malignant cancers.
“Lastly, in mice and humans, a senescence response to strong mitogenic signals, such as those delivered by certain oncogenes, prevents premalignant lesions from progressing to malignant cancers [ 16 – 19 ].”
From Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor (2008) · cites this paper as [18]
The discussion (Nature, vol. 436, 4 August 2005; page not provided) says the findings support oncogene-induced senescence as a mechanism in humans that limits progression of premalignant lesions. The paper studies human melanocytes and naevi, not mice, and describes limitation of progression rather than categorical prevention. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe BRAF oncogenic mutation found in more than half of malignant cutaneous melanomas is also common in non-malignant nevi, where it causes oncogene-induced senescence with high CDKN2A and SA-β-gal expression.
“Additionally, the BRAF oncogenic mutation found in more than half of all malignant cutaneous melanomas is commonly found also in non-malignant nevi, where it causes oncogene-induced senescence exemplified by high levels of CDKN2A and SA-β-gal expression225–227.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [225]
The Abstract and main text report that BRAF V600E is frequent in benign naevi and that sustained expression induces senescence-like arrest with SA-β-Gal activity and increased p16INK4a, the CDKN2A protein. However, the paper does not establish the claimed ‘more than half’ frequency in cutaneous melanomas, and it describes p16INK4a expression in naevi as mosaic rather than uniformly high. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMouse models of melanoma and human nevi show accumulation of SA-β-gal+-CDKN2A+ foci.
“Mouse models of melanoma and human nevi (both oncogene driven) show accumulation of SA-β-gal+–CDKN2A+ foci224,225.”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [225]
In the Nature article’s human-naevi results, all 23 congenital naevi tested showed SA-β-gal activity, and naevi contained p16INK4a-expressing cells (p16INK4a is encoded by CDKN2A). But p16INK4a staining was mosaic, and the paper does not establish an accumulation of uniformly double-positive foci. This source addresses the human-naevi part of the sentence, not the mouse-model part. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOIS is frequently observed in premalignant and benign tumour tissues but not in advanced malignant tumours, where cancer cells have already bypassed senescence.
“This type of oncogene-induced senescence (OIS) is frequently observed in premalignant and benign tumour tissues [37 -39] but not in advanced malignant tumours, where cancer cells have already bypassed senescence.”
From The role of cellular senescence and SASP in tumour microenvironment (2023) · cites this paper as [37]
The paper reports senescence-like arrest in human melanocytic naevi, which are benign lesions, and describes oncogene-induced senescence as limiting progression of premalignant lesions (Abstract; main text, page not provided). It does not establish that OIS is frequent across benign and premalignant tumour tissues generally, or that it is absent from advanced malignant tumours because their cells have bypassed senescence. (LLM, conf=0.87)
Experimental — accuracy not yet measuredHallmarks of senescent cells were subsequently identified in dermal premalignant lesions, specifically human melanocytic naevi.
“Hallmarks of senescent cells were subsequently identified in dermal premalignant lesions, specifically human melanocytic naevi 81,82 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [81]
Studies in various mouse models, supported by correlative evidence from human-derived tissue samples, have underscored the tumour-suppressive role of OIS.
“Studies in various mouse models, supported by correlative evidence from human- derived tissue samples, have underscored the tumour- suppressive role of OIS 81,120-123 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [81]
Oncogene-induced senescence protects against tumor initiation.
“Oncogene-induced senescence protects against tumor initiation 34–37.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [35]
Oncogene-induced senescence acts as a strong tumor suppressor mechanism.
“OIS is a powerful tumor suppressor mechanism 34–37.”
From Cardiac glycosides are broad-spectrum senolytics (2019) · cites this paper as [35]
Cells lacking functional p53 or overexpressing JMJD2c fail to enter VIS and lack a SASP after SARS-CoV-2 infection.
“in vitro experiments showed that cells that lack functional p53 or overexpress the H3K9me3 demethylase JMJD2c46,50 — which therefore cannot enter senescence in response to pro-senescent oncogenes such as Ras-G12V or Braf-V600E46,51 — also failed to enter VIS and lacked a SASP upon infection with SARS-CoV-2 (ref.28).”
From COVID-19 and cellular senescence (2023) · cites this paper as [51]
Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression.
“Studies have demonstrated high levels of senescence in premalignant lesions and lower levels in invasive disease, suggesting a role for senescence in blocking malignant progression [2,31,32].”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [32]
Human melanocytic naevi remain non-proliferative for decades without becoming malignant melanoma, showing that senescence arrest can be tumour suppressive without obvious senescence surveillance.
“human melanocytic naevi (an OIS model), remain non-proliferative for decades without transformation into malignant melanoma 25”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [25]
Michaloglou et al. 2005 identified OIS of human melanocytic naevi.
“This is a seminal study that identified OIS of human melanocytic naevi.”
From Inside and out: the activities of senescence in cancer (2014) · cites this paper as [25]
Senescence markers are detected in premalignant tumor lesions but not at later stages of tumor development.
“Senescence markers are detected in premalignant tumor lesions but not at later stages of tumor development [17,18,19].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [19]
Benign melanocytic lesions, which are melanoma precursors in humans, express high p16 and are an in vivo example of OIS.
“Benign melanocytic lesions, which are melanoma precursors in humans, express high p16 and are an in vivo example of OIS [19,55].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [19]
Such telomeres are not visibly shorter than functional telomeres in human melanocytic nevi with frequent BRAF mutations, a typical OIS feature in vivo.
“Indeed, such telomeres are not visibly shorter than functional telomeres [114] in human melanocytic nevi with frequent BRAF mutations, a typical OIS feature in vivo [19].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [19]
The ARF locus is more commonly deleted or silenced than mutated in melanoma.
“Indeed, its locus is more commonly deleted or silenced than mutated in melanoma, the more malignant later stage of disease [19,55].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [19]
N-RAS- or B-RAF-activating mutations are commonly found in benign melanocytic nevi that show features of senescence, such as elevated p16 levels, but that do not express appreciable levels of ARF or p53.
“For example, N-RAS- or B-RAF-activating mutations are commonly found in benign melanocytic nevi that show features of senescence, such as elevated p16 levels, but that do not express appreciable levels of ARF or p53 [19,55].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [19]
In humans, Ras activation appears to induce only p16.
“In humans, Ras activation appears to induce only p16 [19,127].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [19]
Senescence occurs during formation of benign cutaneous melanocytic nevi that express an oncogenic form of BRAF.
“senescence occurs during the formation of benign cutaneous melanocytic nevi that express an oncogenic form of BRAF [19].”
From Mechanisms and Regulation of Cellular Senescence (2021) · cites this paper as [19]
4N senescent cells occur in human melanocyte naevi, suggesting that the G2 exit program has a more general role in senescence.
“Importantly, this work also provided evidence for the occurrence of 4N senescent cells in human melanocyte naevi, the first in vivo senescence model, 94 suggesting that the G2 exit program has a more general role in senescence.”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [94]
Aberrant activation of oncogenes such as Ras, BRAF V600E, and c-Myc, or loss of tumor suppressor genes such as PTEN, temporarily arrests a large variety of tumors in a pre-malignant state (oncogene-induced senescence).
“The acronym oncogene-induced senescence (OIS) was coined following the demonstration that the aberrant activation of oncogenes (e.g., Ras, BRAF V600E, and c-Myc) or loss of tumor suppressor genes (e.g., PTEN) temporarily arrests a large variety of tumors in a pre-malignant state 180-183 (Figure 3B).”
From Meta-hallmarks of aging and cancer (2023) · cites this paper as [182]
BRAFV600E mutation alone is often insufficient to drive malignant transformation of melanocytes.
“BRAFV600E mutation alone is often insufficient to drive malignant transformation of melanocytes24.”
From Mechanisms and prevention of <scp>UV</scp>‐induced melanoma (2018) · cites this paper as [24]
Developmental senescent cells express p21WAF1/Cip1 but not p16INK4a, while the reverse is observed in melanocytic nevi.
“For example, developmental senescent cells express p21WAF1/Cip1 but not p16INK4a9,10, while the reverse is observed in melanocytic nevi36,37.”
From Algorithmic assessment of cellular senescence in experimental and clinical specimens (2021) · cites this paper as [36]
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- Authors
- Michaloglou, C., Vredeveld, L. C. W., Soengas, M. S., Denoyelle, C., Kuilman, T., van der Horst, C. M. A. M., Majoor, D. M., Shay, J. W., Mooi, W. J., & Peeper, D. S.
- Affiliations
- The Netherlands Cancer Institute (NL)
- University of Michigan (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Mooi, Wolter J.
- Peeper, Daniel S.
- Venue
- Nature
- Published
- 2005-08
- Volume
- 436
- Issue
- 7051
- Pages
- 720-724
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2150740687
- Semantic Scholar
- bfbf433cb25b4a5e054e35a6850376801a03b87d
- Cited by
- 2,160
- References
- 31
- Citations by year
- 2026: 35 · 2025: 43 · 2024: 70 · 2023: 82 · 2022: 77 · 2021: 85 · 2020: 86 · 2019: 108 · 2018: 99 · 2017: 91 · 2016: 121 · 2015: 112 · 2014: 120 · 2013: 143 · 2012: 136
- FWCI
- 66.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- cellular senescence, BRAF V600E mutation, melanocytes, nevi, melanoma, cell cycle arrest, senescence-associated heterochromatin foci, SUV39H1, histone methyltransferase, p16INK4a, p53, PTEN, oncogene-induced senescence, tumor suppression
- MeSH terms
- beta-Galactosidase, Cell Cycle, Cell Line, Fibroblasts, Humans, Infant, Melanocytes, Nevus, Telomere, Cellular Senescence, In Situ Hybridization, Fluorescence, Cyclin-Dependent Kinase Inhibitor p16, Proto-Oncogene Proteins B-raf, Cell Proliferation
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