Maggi Leonard B, Kuchenruether Michael, Dadey David Y A, Schwope Rachel M, Grisendi Silvia, Townsend R Reid, Pandolfi Pier Paolo, Weber Jason D
Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA.
Mol Cell Biol. 2008 Dec;28(23):7050-65. doi: 10.1128/MCB.01548-07. Epub 2008 Sep 22.
Nucleophosmin (NPM) (B23) is an essential protein in mouse development and cell growth; however, it has been assigned numerous roles in very diverse cellular processes. Here, we present a unified mechanism for NPM's role in cell growth; NPM directs the nuclear export of both 40S and 60S ribosomal subunits. NPM interacts with rRNA and large and small ribosomal subunit proteins and also colocalizes with large and small ribosomal subunit proteins in the nucleolus, nucleus, and cytoplasm. The transduction of NPM shuttling-defective mutants or the loss of Npm1 inhibited the nuclear export of both the 40S and 60S ribosomal subunits, reduced the available pool of cytoplasmic polysomes, and diminished overall protein synthesis without affecting rRNA processing or ribosome assembly. While the inhibition of NPM shuttling can block cellular proliferation, the dramatic effects on ribosome export occur prior to cell cycle inhibition. Modest increases in NPM expression amplified the export of newly synthesized rRNAs, resulting in increased rates of protein synthesis and indicating that NPM is rate limiting in this pathway. These results support the idea that NPM-regulated ribosome export is a fundamental process in cell growth.
核磷蛋白（NPM）（B23）是小鼠发育和细胞生长中的一种必需蛋白质；然而，它在非常多样的细胞过程中被赋予了众多作用。在此，我们提出了一种关于NPM在细胞生长中作用的统一机制；NPM指导40S和60S核糖体亚基的核输出。NPM与rRNA以及核糖体大、小亚基蛋白相互作用，并且在核仁、细胞核和细胞质中也与核糖体大、小亚基蛋白共定位。NPM穿梭缺陷突变体的转导或Npm1的缺失抑制了40S和60S核糖体亚基的核输出，减少了细胞质多聚核糖体的可用库，并减少了整体蛋白质合成，而不影响rRNA加工或核糖体组装。虽然抑制NPM穿梭可阻断细胞增殖，但对核糖体输出的显著影响发生在细胞周期抑制之前。NPM表达的适度增加放大了新合成rRNA的输出，导致蛋白质合成速率增加，并表明NPM在该途径中是限速的。这些结果支持了NPM调节的核糖体输出是细胞生长中的一个基本过程这一观点。
