Laboratory for the Study of Skeletal Disorders and Rehabilitation, Department of Orthopedics, Children's Hospital Boston, 300 Longwood Avenue EN926, Boston, MA 02115, USA.
Biochem Biophys Res Commun. 2010 Jun 11;396(4):944-9. doi: 10.1016/j.bbrc.2010.05.028. Epub 2010 May 9.
LOX, the principal enzyme involved in crosslinking of collagen, was the first of several lysyl oxidase isotypes to be characterized. Its active form was believed to be exclusively extracellular. Active LOX was later reported to be present in cell nuclei; its function there is unknown. LOX expression opposes the effect of mutationally activated Ras, which is present in about 30% of human cancers. The mechanism of LOX in countering the action of Ras is also unknown. In the present work, assessment of nuclear protein for possible effects of lysyl oxidase activity led to the discovery that proliferating cells dramatically increase their nuclear protein content when exposed to BAPN (beta-aminopropionitrile), a highly specific lysyl oxidase inhibitor that reportedly blocks LOX inhibition of Ras-induced oocyte maturation. In three cell types (PC12 cells, A7r5 smooth muscle cells, and NIH 3T3 fibroblasts), BAPN caused a 1.8-, 1.7-, and 2.1-fold increase in total nuclear protein per cell, respectively, affecting all major components in both nuclear matrix and chromatin fractions. Since nuclear size is correlated with proliferative status, enzyme activity restricting nuclear growth may be involved in the lysyl oxidase tumor suppressive effect. Evidence is also presented for the presence of apparent lysyl oxidase isotype(s) containing a highly conserved LOX active site sequence in the nuclei of PC12 cells, which do not manufacture extracellular lysyl oxidase substrates. Results reported here support the hypothesis that nuclear lysyl oxidase regulates nuclear growth, and thereby modulates cell proliferation.
赖氨酰氧化酶（LOX）是参与胶原蛋白交联的主要酶，是首批被鉴定的几种赖氨酰氧化酶同工酶之一。其活性形式被认为仅存在于细胞外。后来有报道称活性 LOX 存在于细胞核中；其功能尚不清楚。LOX 的表达与突变激活的 Ras 相反，Ras 存在于大约 30%的人类癌症中。LOX 对抗 Ras 作用的机制也不清楚。在本研究中，评估核蛋白中赖氨酰氧化酶活性的可能影响，导致发现增殖细胞在暴露于 BAPN（β-氨基丙腈）时，其细胞核蛋白含量会显著增加，BAPN 是一种高度特异性的赖氨酰氧化酶抑制剂，据报道可阻止 LOX 抑制 Ras 诱导的卵母细胞成熟。在三种细胞类型（PC12 细胞、A7r5 平滑肌细胞和 NIH 3T3 成纤维细胞）中，BAPN 分别使每个细胞的总核蛋白增加 1.8、1.7 和 2.1 倍，影响核基质和染色质部分的所有主要成分。由于核大小与增殖状态相关，因此限制核生长的酶活性可能与赖氨酰氧化酶的肿瘤抑制作用有关。还提供了证据表明，在不产生细胞外赖氨酰氧化酶底物的 PC12 细胞核中存在具有高度保守 LOX 活性位点序列的明显赖氨酰氧化酶同工酶。本文报道的结果支持了核赖氨酰氧化酶调节核生长，从而调节细胞增殖的假说。
