A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation
A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation
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DOI：
10.1073/pnas.0403250101
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发表时间：
2004-06-29
影响因子：
11.1
通讯作者：
Kennedy, BK
中科院分区：
文献类型：
--
作者：
Johnson, BR;Nitta, RT;Kennedy, BK
视网膜母细胞瘤蛋白（retinoblastoma protein, pRB）是细胞增殖和分化的重要调控因子，也是重要的肿瘤抑制因子。在细胞周期的G(1)期，pRB定位于核内与核内纤层蛋白A/C相关的核周位点。在这里，我们研究了缺乏层合蛋白A/C的细胞中pRB的功能，发现pRB水平急剧下降，剩余的pRB定位错误。我们证明了a型纤层蛋白保护pRB免受蛋白酶体降解。在重新引入层合蛋白a后，pRB水平和定位都得到恢复。Lmna（-/-）细胞与Rb-/-细胞相似，表现出细胞周期特性的改变，并且在DNA损伤的反应中，细胞周期阻滞的能力降低。这些发现在核心核结构成分和重要的细胞周期调节因子之间建立了功能联系。他们进一步提出了pRB功能改变可能是由LMNA突变引起的营养不良综合征的一个促成因素的可能性。
The retinoblastoma protein (pRB) is a critical regulator of cell proliferation and differentiation and an important tumor suppressor. In the G(1) phase of the cell cycle, pRB localizes to perinucleolar sites associated with lamin A/C intranuclear foci. Here, we examine pRB function in cells lacking lamin A/C, finding that pRB levels are dramatically decreased and that the remaining pRB is mislocalized. We demonstrate that A-type lamins protect pRB from proteasomal degradation. Both pRB levels and localization are restored upon reintroduction of lamin A. Lmna(-/-) cells resemble Rb-/- cells, exhibiting altered cell-cycle properties and reduced capacity to undergo cell-cycle arrest in response to DNA damage. These findings establish a functional link between a core nuclear structural component and an important cell-cycle regulator. They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation.