Fresa K, Hameed M, Cohen S
Department of Pathology, Hahnemann University, Philadelphia, Pennsylvania 19102-1192.
Clin Immunol Immunopathol. 1989 Jan;50(1 Pt 1):8-19. doi: 10.1016/0090-1229(89)90217-1.
Activation of lymphocytes for proliferation is associated with the appearance of an intracellular factor (ADR) that can induce DNA synthesis in isolated quiescent nuclei. ADR plays a role in the sequence of intracellular events leading to activation for IL-2-mediated proliferation. Because of the nature of the defining assay, the locus of ADR action appears to be near the terminal end of the transduction pathway. Interestingly, although lymphocytes from aged individuals respond poorly to proliferative stimuli, they appear to produce normal to above-normal levels of ADR. In contrast, their nuclei are only poorly responsive to stimulation by ADR. Preparations rich in ADR activity have proteolytic activity as well. In addition, aprotinin, as well as a variety of other protease inhibitors, suppresses ADR-induced DNA synthesis in a dose-dependent manner. ADR activity can be removed from active extracts by absorption with aprotinin-conjugated agarose beads, and can be removed from the beads by elution at pH 5.0. This latter suggests that ADR itself is a protease. However, its endogenous substrate is not yet known. We have also detected an inhibitor of ADR activity in the cytoplasm of resting lymphocytes. This is a heat-stable protein of approximately 60,000 Da. In addition to suppressing the interaction of ADR with quiescent nuclei, the inhibitor can suppress DNA synthetic activity of replicative nuclei isolated from mitogen-activated lymphocytes. Interestingly, these preparations had little or no activity on replicative nuclei derived from several neoplastic cell lines. The resistance of tumor cell nuclei to spontaneously occurring cytoplasmic inhibitory factors such as the one described here may provide one explanation for the loss of growth control in neoplastic cells.
淋巴细胞增殖的激活与一种细胞内因子（ADR）的出现有关，该因子可在分离的静止细胞核中诱导DNA合成。ADR在导致IL-2介导的增殖激活的细胞内事件序列中发挥作用。由于定义性检测的性质，ADR的作用位点似乎位于转导途径的末端附近。有趣的是，尽管老年个体的淋巴细胞对增殖刺激反应不佳，但它们产生的ADR水平似乎正常或高于正常水平。相比之下，它们的细胞核对ADR刺激的反应很差。富含ADR活性的制剂也具有蛋白水解活性。此外，抑肽酶以及多种其他蛋白酶抑制剂以剂量依赖的方式抑制ADR诱导的DNA合成。ADR活性可以通过用抑肽酶偶联的琼脂糖珠吸附从活性提取物中去除，并可以通过在pH 5.0下洗脱从珠子中去除。后者表明ADR本身是一种蛋白酶。然而，其内源性底物尚不清楚。我们还在静止淋巴细胞的细胞质中检测到了一种ADR活性抑制剂。这是一种分子量约为60,000 Da的热稳定蛋白。除了抑制ADR与静止细胞核的相互作用外，该抑制剂还可以抑制从有丝分裂原激活的淋巴细胞中分离的复制细胞核的DNA合成活性。有趣的是，这些制剂对几种肿瘤细胞系来源的复制细胞核几乎没有活性。肿瘤细胞核对自发产生的细胞质抑制因子（如此处所述）的抗性可能为肿瘤细胞生长控制的丧失提供一种解释。
