人骨髓性白血病细胞（即HL-60、U937、THP-1）在受到12-O-四十六内酯-13- 醋酸酯（TPA）单核细胞分化诱导后，经过3到4周可以恢复到未分化表型。在这个分化和反向分化的过程中，细胞显然建立了一个独特的生物过程序列，其完整调节以同时控制分化和细胞生长。因此，TPA诱导的单核标记物与细胞周期基因的下调和增殖停止有关。特别是，TPA诱导的蛋白激酶C（PKC）的横向作用以及转录因子的激活，特别是AP-1，增强了与单核表型相关的基因表达。这伴随着中间纤维蛋白、表面糖蛋白的诱导，膜性质和细胞内代谢的变化。同时，细胞停止分裂，与细胞周期进程相关的cdc2、cyclins、cdc25和组蛋白等基因被下调。尽管有关停滞细胞生长的信号尚不清楚，但有几种关于细胞周期基因和分化参数的控制机制（有关细节，参见Nigg，E.A.，细胞生物学论坛，2，262-270，1991）。例如，活化的p34cdc2激酶通过直接磷酸化层蛋白参与层的解体，这可能有助于有丝分裂期间的核膜破裂（Enoch，T.，M. Peter，P. Nurse，J 。细胞生物学。112，797-807（1991））。此外，通过磷酸化小泡蛋白家族成员来对内质网流量进行阻止，可能会通过水解GTP来促进小泡化和膜运输（Tuomikoski，T。等人，自然342 ，942-945（1989））。尽管有几篇关于分化和细胞周期之间可能存在反馈控制的报道，包括cyclins磷酸化和泛素依赖性蛋白酶降解的激活，但分泌信号通路和反向分化以及重新进入细胞周期的可能机制仍不清楚。虽然一些终末分化的细胞已经确定必须死亡，但大部分分化单核细胞人群会经历反向分化。在反向分化期间，所有已知的细胞信号都会逆转：PKC的重新分布和c-fos、c-jun的下调有助于中断分化相关的跨信号级联。因此，与单核细胞分化相关的标记物的降低结合代谢变化可恢复原始细胞表型。同时，细胞周期基因被上调，细胞恢复了增殖能力。最后，经过反向分化和未经处理的对照细胞表现出无法区分的属性。

Human myeloid leukemia cells (i.e., HL-60, U937, THP-1) which are induced to differentiate along the monocytic pathway by 12-O-tetradecanoylphorbol-13-acetate (TPA), revert back to the undifferentiated phenotype after 3 to 4 weeks. During this differentiation and retrodifferentiation process the cells obviously establish a distinct sequence of biological processes which is integrally regulated to simultaneously control differentiation and cell growth. Thus, induction of monocytic markers by TPA is associated with a down-regulation of cell cycle genes and cessation of proliferation. In particular, crosstalk between the TPA-induced translocation of protein kinase C (PKC) and the activation of transcription factors, especially AP-1, enhances the expression of genes associated with the monocytic phenotype. This is accompanied by induction of intermediate filament proteins, surface glycoproteins, changes in membrane properties and intracellular metabolism. In parallel, the cells cease to divide, and genes associated with cell cycle progression including cdc2, cyclins, cdc25, and histones are down-regulated. Although signals responsible for arrested cell growth remain unclear, there are several control mechanisms regarding cell cycle genes and differentiation parameters (for a review, see Nigg, E. A., Seminars in Cell Biol., 2, 262-270, 1991). For example, activated p34cdc2 kinase is involved in lamina disassembly by direct phosphorylation of lamin proteins which may contribute to nuclear envelope breakdown during mitosis (Enoch, T., M. Peter, P. Nurse, J. Cell Biol. 112, 797-807 (1991)). Moreover, endomembrane traffic is arrested by a cdc2-like kinase probably via phosphorylation of members of the rab protein family which contributes to vesiculation and membrane transport by hydrolyzing GTP (Tuomikoski, T., et al., Nature 342, 942-945 (1989)). Although there are several reports on a possible feedback control between differentiation and cell cycle, including phosphorylation of cyclins and activation of a ubiquitin-dependent proteolytic degradation, signaling pathways and possible mechanisms for retrodifferentiation and reentry into the cell cycle remain unclear. While some terminally differentiated cells are committed to die, the major part of the differentiated monocytic population undergoes retrodifferentiation. All cellular signals characterized so far are reverted during retrodifferentiation: Redistribution of PKC and down-regulation of c-fos and c-jun contribute to an interruption of the differentiation-associated transsignaling cascade. Thus, down-regulation of markers associated with monocytic differentiation in combination with metabolic changes restore the original cell phenotype. At the same time cell cycle genes are up-regulated, and the cells regain proliferative capacity. Finally, retrodifferentiated and untreated control cells demonstrate indistinguishable properties.