Department of Histology and Embryology, Shandong University School of Medicine, Jinan, Shandong, China.
PLoS One. 2010 May 28;5(5):e10874. doi: 10.1371/journal.pone.0010874.
Lamin A (LaA) is a component of the nuclear lamina, an intermediate filament meshwork that underlies the inner nuclear membrane (INM) of the nuclear envelope (NE). Newly synthesized prelamin A (PreA) undergoes extensive processing involving C-terminal farnesylation followed by proteolysis yielding non-farnesylated mature lamin A. Different inhibitors of these processing events are currently used therapeutically. Hutchinson-Gilford Progeria Syndrome (HGPS) is most commonly caused by mutations leading to an accumulation of a farnesylated LaA isoform, prompting a clinical trial using farnesyltransferase inhibitors (FTI) to reduce this modification. At therapeutic levels, HIV protease inhibitors (PI) can unexpectedly inhibit the final processing step in PreA maturation. We have examined the dynamics of LaA processing and associated cellular effects during PI or FTI treatment and following inhibitor washout. While PI reversibility was rapid, with respect to both LaA maturation and associated cellular phenotype, recovery from FTI treatment was more gradual. FTI reversibility is influenced by both cell type and rate of proliferation. These results suggest a less static lamin network than has previously been observed.
核纤层 A（LaA）是核纤层的一个组成部分，核纤层是核膜（NE）内核膜（INM）下的中间丝网格。新合成的前核纤层 A（PreA）经历广泛的加工，包括 C 端法尼基化，然后进行蛋白水解，生成非法尼基化的成熟核纤层 A。目前，这些加工事件的不同抑制剂被用于治疗。亨廷顿舞蹈病-吉尔福德早衰综合征（HGPS）最常见于导致法尼基化 LaA 同工型积累的突变，促使使用法尼基转移酶抑制剂（FTI）进行临床试验以减少这种修饰。在治疗水平上，HIV 蛋白酶抑制剂（PI）可能会意外地抑制 PreA 成熟的最后一个加工步骤。我们已经研究了在 PI 或 FTI 处理以及抑制剂洗脱后 LaA 加工和相关细胞效应的动力学。虽然 PI 的逆转性很快，无论是 LaA 成熟还是相关的细胞表型，从 FTI 治疗的恢复都更加缓慢。FTI 的逆转性受细胞类型和增殖速度的影响。这些结果表明，与以前观察到的相比，层粘连蛋白网络的稳定性较差。
