A-type lamins regulate retinoblastoma protein function by promoting subnuclear localization and preventing proteasomal degradation

作者：Brett Johnson, Ryan T. Nitta, Richard L. Frock, Leslie C. Mounkes, David A. Barbie, Colin L. Stewart, Ed Harlow, Brian K. Kennedy · 发表于：Proceedings of the National Academy of Sciences · 年份：2004 · DOI：10.1073/pnas.0403250101 · 被引用次数：282 · 研究领域：Nuclear Structure and Function、Genomics and Chromatin Dynamics、RNA Research and Splicing

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.