Naetar Nana, Korbei Barbara, Kozlov Serguei, Kerenyi Marc A, Dorner Daniela, Kral Rosana, Gotic Ivana, Fuchs Peter, Cohen Tatiana V, Bittner Reginald, Stewart Colin L, Foisner Roland
Max F. Perutz Laboratories, Medical University of Vienna and University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria.
Nat Cell Biol. 2008 Nov;10(11):1341-8. doi: 10.1038/ncb1793. Epub 2008 Oct 12.
Lamina-associated polypeptide (LAP) 2alpha is a chromatin-associated protein that binds A-type lamins. Mutations in both LAP2alpha and A-type lamins are linked to human diseases called laminopathies, but the molecular mechanisms are poorly understood. The A-type lamin-LAP2alpha complex interacts with and regulates retinoblastoma protein (pRb), but the significance of this interaction in vivo is unknown. Here we address the function of the A-type lamin-LAP2alpha complex with the use of LAP2alpha-deficient mice. We show that LAP2alpha loss causes relocalization of nucleoplasmic A-type lamins to the nuclear envelope and impairs pRb function. This causes inefficient cell-cycle arrest in dense fibroblast cultures and hyperproliferation of epidermal and erythroid progenitor cells in vivo, leading to tissue hyperplasia. Our results support a disease-relevant model in which LAP2alpha defines A-type lamin localization in the nucleoplasm, which in turn affects pRb-mediated regulation of progenitor cell proliferation and differentiation in highly regenerative tissues.
核纤层相关多肽（LAP）2α是一种与染色质相关的蛋白质，可与A型核纤层蛋白结合。LAP2α和A型核纤层蛋白的突变均与称为核纤层病的人类疾病有关，但分子机制尚不清楚。A型核纤层蛋白-LAP2α复合物与视网膜母细胞瘤蛋白（pRb）相互作用并对其进行调节，但这种相互作用在体内的意义尚不清楚。在这里，我们利用LAP2α缺陷小鼠来研究A型核纤层蛋白-LAP2α复合物的功能。我们发现，LAP2α的缺失会导致核质中的A型核纤层蛋白重新定位到核膜，并损害pRb的功能。这导致致密成纤维细胞培养物中的细胞周期阻滞效率低下，以及体内表皮和红系祖细胞的过度增殖，从而导致组织增生。我们的结果支持一种与疾病相关的模型，即LAP2α决定了A型核纤层蛋白在核质中的定位，进而影响pRb介导的对高再生组织中祖细胞增殖和分化的调节。
