Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi.
Dynamic assembly of chromatin complexes during cellular senescence: implications for the growth arrest of human melanocytic nevi.
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DOI：
10.1111/j.1474-9726.2007.00308.x
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发表时间：
2007-08
期刊：
影响因子：
7.8
通讯作者：
Medrano EE
中科院分区：
文献类型：
--
作者：
Bandyopadhyay D;Curry JL;Lin Q;Richards HW;Chen D;Hornsby PJ;Timchenko NA;Medrano EE
视网膜母细胞瘤（RB）/p16 INK 4a通路调节培养的人黑素细胞衰老和体内黑素细胞痣癌基因诱导的衰老这种衰老反应可能是由于染色质修饰，因为来自衰老黑素细胞的RB复合物含有增加水平的组蛋白脱乙酰酶（HDAC）活性和束缚的HDAC 1。在这里，我们发现，HDAC 1显着检测p16 INK 4a阳性，衰老的皮内黑色素细胞痣，但不增殖，复发痣细胞定位于表皮/真皮交界处。为了评估HDAC 1在黑素细胞和痣衰老中的作用，我们在培养的黑素细胞中使用基于四环素的诱导型表达系统。我们发现HDAC 1驱动染色质重塑效应物的顺序和合作活性，包括Brahma（Brm 1）瞬时募集到RB/HDAC 1 mega-复合物中，异染色质蛋白1β（HP 1 β）/SUV 39 H1灶的形成，H3-K9的甲基化，RB与染色质的稳定缔合和显著的全局异染色质化。这些染色质变化与衰老的典型标志物的表达一致，包括衰老相关的β-半乳糖苷酶标志物。值得注意的是，RB/HP 1 β灶的形成和RB与染色质的早期拴系依赖于完整的Brm 1 ATP酶活性。随着细胞衰老，Brm 1从染色质中排出，与其从HP 1 β/RB中解离并重新定位于较低分子量的蛋白质复合物相一致。这些结果为RB通路在调节细胞衰老中的作用提供了新的见解，并暗示HDAC 1可能是早期染色质重塑事件的介导者。
The retinoblastoma (RB)/p16INK4a pathway regulates senescence of human melanocytes in culture and oncogene-induced senescence of melanocytic nevi in vivo. This senescence response is likely due to chromatin modifications because RB complexes from senescent melanocytes contain increased levels of histone deacetylase (HDAC) activity and tethered HDAC1. Here we show that HDAC1 is prominently detected in p16INK4a-positive, senescent intradermal melanocytic nevi but not in proliferating, recurrent nevus cells that localize to the epidermal/dermal junction. To assess the role of HDAC1 in the senescence of melanocytes and nevi, we used tetracycline-based inducible expression systems in cultured melanocytic cells. We found that HDAC1 drives a sequential and cooperative activity of chromatin remodeling effectors, including transient recruitment of Brahma (Brm1) into RB/HDAC1 mega-complexes, formation of heterochromatin protein 1β (HP1β)/SUV39H1 foci, methylation of H3-K9, stable association of RB with chromatin and significant global heterochromatinization. These chromatin changes coincide with expression of typical markers of senescence, including the senescent-associated β-galactosidase marker. Notably, formation of RB/HP1β foci and early tethering of RB to chromatin depends on intact Brm1 ATPase activity. As cells reached senescence, ejection of Brm1 from chromatin coincided with its dissociation from HP1β/RB and relocalization to protein complexes of lower molecular weight. These results provide new insights into the role of the RB pathway in regulating cellular senescence and implicate HDAC1 as a likely mediator of early chromatin remodeling events.
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DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
5.3
作者：
Barbie, DA;Kudlow, BA;Kennedy, BK
通讯作者：
Kennedy, BK
影响因子：
11.4
作者：
Aagaard, L;Laible, G;Jenuwein, T
通讯作者：
Jenuwein, T
影响因子：
64.8
作者：
Conboy, IM;Conboy, MJ;Rando, TA
通讯作者：
Rando, TA
影响因子：
4
作者：
Hayakawa, T;Haraguchi, T;Hiraoka, Y
通讯作者：
Hiraoka, Y