Somech Raz, Gal-Yam Einav Nili, Shaklai Sigal, Geller Orit, Amariglio Ninette, Rechavi Gideon, Simon Amos J
Sheba Cancer Research Center, Institute of Hematology, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Ann Hematol. 2007 Jun;86(6):393-401. doi: 10.1007/s00277-007-0275-9. Epub 2007 Mar 16.
Extensive research in recent years has broadened the functions of nuclear envelope proteins beyond simply stabilizing the nucleus architecture. Particularly, integral nuclear membrane proteins, such as the alternative spliced isoforms of lamina-associated polypeptide 2 (LAP2), have been shown to be important for the initiation of replication and repression of transcription. The latter is regulated by epigenetic changes, induced by the binding of LAP2beta to histone deacetylase-3 (HDAC3), resulting in histone H4 deacetylation. Involvement of nuclear envelope proteins in pathological proliferative conditions, mainly those involving abnormal recruitment and activation of HDACs, is still unknown. In this paper, we show that various nuclear envelope proteins are highly expressed in normal and malignant activated lymphocytes. Specifically, rapidly replicating cells of various hematological malignancies highly express LAP2beta, while slowly proliferating malignant cells of chronic malignant hematological diseases do not. Taking together the elevated expression of LAP2beta in highly proliferative malignant cells with its known ability to modify histones through binding with HDAC3 raises the possibility of its role in hematological malignancies involving aberrant activity of HDAC3. Based on our presented results, we believe that the LAP2-HDAC regulatory pathway should be studied as a new target for rational therapy.
近年来的大量研究拓宽了核膜蛋白的功能，其作用不再仅仅局限于稳定细胞核结构。特别是，核膜整合蛋白，如核纤层相关多肽2（LAP2）的可变剪接异构体，已被证明对复制起始和转录抑制很重要。后者由LAP2β与组蛋白脱乙酰基酶-3（HDAC3）结合诱导的表观遗传变化调控，导致组蛋白H4去乙酰化。核膜蛋白在病理性增殖状态中的作用，主要是那些涉及HDAC异常募集和激活的状态，目前仍不清楚。在本文中，我们表明多种核膜蛋白在正常和恶性激活的淋巴细胞中高度表达。具体而言，各种血液系统恶性肿瘤中快速复制的细胞高度表达LAP2β，而慢性恶性血液疾病中缓慢增殖的恶性细胞则不表达。鉴于LAP2β在高度增殖的恶性细胞中表达升高，以及其通过与HDAC3结合修饰组蛋白的已知能力，这增加了其在涉及HDAC3异常活性的血液系统恶性肿瘤中发挥作用的可能性。基于我们给出的结果，我们认为LAP2-HDAC调节通路应作为合理治疗的新靶点进行研究。
