Kiyokawa H, Richon V M, Venta-Perez G, Rifkind R A, Marks P A
Program of Cell Biology and Genetics, DeWitt Wallace Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY.
Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6746-50. doi: 10.1073/pnas.90.14.6746.
Hexamethylenebisacetamide (HMBA), a potent inducer of differentiation of transformed cells such as murine erythroleukemia cells, causes a prolongation of the G1 phase of the cell cycle during which commitment to terminal differentiation is first detected. Removal of HMBA prior to the G1 phase aborts commitment. To further define the relationship between the G1 phase and commitment to differentiation, we used two inhibitors of cell cycle progression: aphidicolin, which blocks cells at the G1/S interphase, and deferoxamine, which blocks cells at an earlier stage during G1. HMBA-induced prolongation of G1 is associated with the accumulation of underphosphorylated retinoblastoma protein, decrease in cyclin A protein levels, and commitment to differentiation. G1 arrest of murine erythroleukemia cells induced by aphidicolin or deferoxamine is not associated with accumulation of under-phosphorylated retinoblastoma protein, suppression of cyclin A protein, or commitment of cells to terminal differentiation. Neither of the cell cycle inhibitors alters the effect of HMBA in inducing the G1-associated changes or commitment to differentiation. Taken together, the present findings indicate that the site of action of HMBA which leads to commitment is in a stage of the G1 phase prior to the point of cell cycle block caused by deferoxamine or aphidicolin. HMBA appears to cause cell differentiation with suppression of cell cycle progression by an action that affects events required for cell progression through G1, including accumulation of underphosphorylated retinoblastoma protein and changes in regulation of cyclin levels.
六亚甲基双乙酰胺（HMBA）是一种有效的转化细胞分化诱导剂，如鼠红细胞白血病细胞，它会导致细胞周期的G1期延长，在此期间首次检测到细胞向终末分化的定向。在G1期之前去除HMBA会终止细胞定向。为了进一步确定G1期与分化定向之间的关系，我们使用了两种细胞周期进程抑制剂：阿非科林，它将细胞阻滞在G1/S间期；去铁胺，它在G1期的更早阶段阻滞细胞。HMBA诱导的G1期延长与低磷酸化视网膜母细胞瘤蛋白的积累、细胞周期蛋白A蛋白水平的降低以及分化定向有关。由阿非科林或去铁胺诱导的鼠红细胞白血病细胞的G1期阻滞与低磷酸化视网膜母细胞瘤蛋白的积累、细胞周期蛋白A的抑制或细胞向终末分化的定向无关。这两种细胞周期抑制剂都不会改变HMBA诱导与G1相关变化或分化定向的作用。综上所述，目前的研究结果表明，导致细胞定向的HMBA作用位点在G1期的一个阶段，该阶段早于去铁胺或阿非科林引起的细胞周期阻滞点。HMBA似乎通过影响细胞通过G1期所需的事件来抑制细胞周期进程，从而导致细胞分化，这些事件包括低磷酸化视网膜母细胞瘤蛋白的积累和细胞周期蛋白水平调节的变化。
