Coffman F D, Fresa K L, Cohen S
Department of Pathology, Hahnemann University, Philadelphia, Pennsylvania 19102-1192.
J Cell Biochem. 1991 Jan;45(1):15-21. doi: 10.1002/jcb.240450107.
The initiation of DNA replication in T lymphocytes appears to be regulated by two distinct activities: one associated with proliferation which mediates initiation, and another associated with quiescence which blocks initiation. Activated lymphocytes and proliferating lymphoid cell lines produce an activity, termed ADR, which can initiate DNA replication in isolated, quiescent nuclei. ADR is heat-labile, has protease activity or interacts closely with a protease, and is distinct from the DNA polymerases. ADR activity is absent in quiescent lymphocytes and appears in mitogen-stimulated lymphocytes after IL-2 binding. The generation of active ADR appears to be mediated by phosphorylation of a precursor which is present in resting cells. Nuclei from mitogen-unresponsive lymphocytes fail to initiate DNA replication in response to ADR, of potential importance in the age-related decline of immunity. Quiescent lymphocytes lack ADR and synthesize an ADR-inhibitory activity. The ADR inhibitor is a heat-stable protein which suppresses the initiation of DNA synthesis, but is ineffective at suppressing elongation once DNA strand replication has begun. Nuclei from several neoplastic cell lines fail to respond to the ADR inhibitor, which may play a role in the continuous proliferation of these cells. At least one of these neoplastic cell lines produces both ADR and an inhibitory factor. These findings suggest that the regulation of proliferation is dependent on the balance between activating and inhibitory pathways.
T淋巴细胞中DNA复制的起始似乎受两种不同活性的调节：一种与介导起始的增殖相关，另一种与阻断起始的静止相关。活化的淋巴细胞和增殖的淋巴细胞系产生一种称为ADR的活性物质，它能在分离的静止细胞核中起始DNA复制。ADR对热不稳定，具有蛋白酶活性或与一种蛋白酶密切相互作用，并且与DNA聚合酶不同。静止淋巴细胞中不存在ADR活性，在白细胞介素-2结合后，有丝分裂原刺激的淋巴细胞中会出现ADR活性。活性ADR的产生似乎是由静止细胞中存在的一种前体的磷酸化介导的。对有丝分裂原无反应的淋巴细胞的细胞核不能响应ADR起始DNA复制，这在与年龄相关的免疫衰退中可能具有潜在重要性。静止淋巴细胞缺乏ADR并合成一种ADR抑制活性物质。ADR抑制剂是一种热稳定蛋白，它能抑制DNA合成的起始，但一旦DNA链复制开始，在抑制延伸方面无效。几种肿瘤细胞系的细胞核对ADR抑制剂无反应，这可能在这些细胞的持续增殖中起作用。至少其中一种肿瘤细胞系同时产生ADR和一种抑制因子。这些发现表明，增殖的调节取决于激活途径和抑制途径之间的平衡。
