BRAFE600-associated senescence-like cell cycle arrest of human naevi
BRAFE600-associated senescence-like cell cycle arrest of human naevi
复制标题
DOI：
10.1038/nature03890
复制
发表时间：
2005-08-04
期刊：
影响因子：
64.8
通讯作者：
Peeper, DS
中科院分区：
文献类型：
--
作者：
Michaloglou, C;Vredeveld, LCW;Peeper, DS
大多数正常哺乳动物细胞的寿命是有限的(1)，这被认为构成了防止无限增殖的保护机制(2-4)。这种现象称为衰老，是由端粒磨损驱动的，端粒磨损会触发包括 p16(INK4a) 在内的肿瘤抑制因子的诱导（参考文献 5）。在培养的细胞中，癌基因可导致过早衰老 (6)；然而，这种癌基因诱导的衰老是否代表一种生理过程长期以来一直存在争议。人痣（痣）是黑素细胞的良性肿瘤，经常在 BRAF(7)（一种蛋白激酶和 Ras 下游效应子）中携带致癌突变（主要是 V600E，其中缬氨酸取代了谷氨酸）。尽管如此，痣通常会在几十年内保持生长停滞状态，并且很少进展为恶性肿瘤（黑色素瘤）(8-10)。这就提出了一个问题：痣是否会经历 BRAF(V600E) 诱导的衰老。在这里，我们表明，人黑素细胞中持续表达 BRAF(V600E) 会诱导细胞周期停滞，同时诱导 p16(INK4a) 和衰老相关的酸性 β-半乳糖苷酶 (SA-β-Gal) 活性（一种常用的衰老标记物）。在体内验证这些结果，先天性痣总是 SA-β-Gal 呈阳性，证明这种经典的衰老相关标记物存在于大部分生长停滞的肿瘤人类病变中。在体外和原位生长停滞的黑素细胞中，我们观察到 p16(INK4a) 的显着马赛克诱导，表明 p16(INK4a) 以外的因素有助于防止 BRAF(V600E) 驱动的增殖。痣似乎没有受到端粒磨损的影响，认为有利于活跃的癌基因驱动的衰老过程，而不是复制潜力的丧失。因此，在体外和体内，表达 BRAF(V600E) 的黑素细胞都显示出衰老的经典标志，表明癌基因诱导的衰老代表了真正的保护性生理过程。
Most normal mammalian cells have a finite lifespan(1), thought to constitute a protective mechanism against unlimited proliferation(2-4). 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(6); 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(7), 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)(8-10). 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.