Shackney S E, Shankey T V
Department of Human Oncology and Human Genetics, Allegheny University of the Health Sciences, Pittsburgh, Pennsylvania 15212, USA.
Cytometry. 1999 Feb 1;35(2):97-116. doi: 10.1002/(sici)1097-0320(19990201)35:2<97::aid-cyto1>3.3.co;2-x.
Some cell cycle models assume that cells are normally in a quiescent state until they are stimulated to enter the cell cycle and proceed through an S phase of fixed duration. Other models assume that cells normally cycle rapidly until they undergo growth retardation, proceed through an S phase of longer duration, and then undergo apoptosis or cell differentiation preferentially. These seemingly contradictory model types can be reconciled by restricting the latter type to the transition from log phase to plateau phase growth, and the former type to the recruitment of slowly proliferating cells into rapid cycle. Both proliferative states can be unified in a single cell cycle model that recognizes differences in the behavior of rapidly dividing and slowly dividing cells in the same population. Rb appears to play a major role in protecting slowly proliferating cells from apoptosis, permitting them to differentiate or persist as reserve cells that can be recruited into rapid cycle under appropriate circumstances. We examine the mechanistic basis for the recruitment phenomenon in some detail. The mitogenic signaling pathway is divided into a proximal segment, which consists of growth factor-induced membrane signaling, commonly through ras, raf, and cyclin D/cdk Rb kinase activation, and is subject to checks and balances that are designed to limit the propagation of the mitogenic signal. ras and raf compete with wild-type p53 both with respect to mitogenic signal propagation at the Rb node, and, separately, with respect to apoptosis/anti-apoptosis. The distal segment of the mitogenic signaling pathway, which consists of Rb phosphorylation, the release of E2F, the induction of c-myc, cyclins E and A, and DNA synthesis, is distinguished by a multiplicity of nested positive feedback loops; these would be expected to drive a mitogenic signal that entered the distal segment through at least one round of DNA synthesis. Using this model, we can identify two separate mechanistic strategies for neoplastic transformation. Chronic mitogenic stimulation of slowly proliferating cells would appear to be a common feature of Rb +/+ tumors. Rb -/- tumors dispense with the early segment of the mitogenic signaling pathway and its anti-apoptotic features, and maintain rapid cell cycling to compensate for high apoptotic rates.
一些细胞周期模型假设，细胞通常处于静止状态，直到受到刺激进入细胞周期并经历固定时长的S期。其他模型则假设，细胞通常快速循环，直到经历生长迟缓，进入持续时间更长的S期，然后优先经历凋亡或细胞分化。通过将后一种模型类型限制在对数期到平台期生长的转变，而将前一种模型类型限制在将缓慢增殖细胞招募到快速循环中，可以调和这些看似矛盾的模型类型。两种增殖状态可以统一在一个单细胞周期模型中，该模型认识到同一群体中快速分裂和缓慢分裂细胞行为的差异。Rb似乎在保护缓慢增殖细胞免于凋亡方面发挥主要作用，使其能够分化或作为储备细胞持续存在，在适当情况下可被招募进入快速循环。我们详细研究了招募现象的机制基础。有丝分裂信号通路分为近端部分，其由生长因子诱导的膜信号传导组成，通常通过ras、raf以及细胞周期蛋白D/细胞周期蛋白依赖性激酶Rb激酶激活，并且受到旨在限制有丝分裂信号传播的制衡。ras和raf在Rb节点处的有丝分裂信号传播方面以及在凋亡/抗凋亡方面分别与野生型p53竞争。有丝分裂信号通路的远端部分由Rb磷酸化、E2F释放、c-myc、细胞周期蛋白E和A的诱导以及DNA合成组成，其特点是有多个嵌套的正反馈环；预计这些正反馈环将驱动通过至少一轮DNA合成进入远端部分的有丝分裂信号。使用该模型，我们可以识别肿瘤转化的两种独立机制策略。对缓慢增殖细胞的慢性有丝分裂刺激似乎是Rb +/+肿瘤的一个共同特征。Rb -/-肿瘤省去了有丝分裂信号通路的早期部分及其抗凋亡特征，并维持快速细胞循环以补偿高凋亡率。
