Kang C D, Do I R, Kim K W, Ahn B K, Kim S H, Chung B S, Jhun B H, Yoo M A
Pusan Cancer Research Center, Pusan National University, Korea.
Exp Mol Med. 1999 Jun 30;31(2):76-82. doi: 10.1038/emm.1999.13.
The chronic myelogenous leukemic K562 cell line carrying Bcr-Abl tyrosine kinase is considered as pluripotent hematopoietic progenitor cells expressing markers for erythroid, granulocytic, monocytic, and megakaryocytic lineages. Here we investigated the signaling modulations required for induction of erythroid differentiation of K562 cells. When the K562 cells were treated with herbimycin A (an inhibitor of protein tyrosine kinase), ras antisense oligonucleotide, and PD98059 (a specific inhibitor of MEK), inhibition of ERK/MAPK activity and cell growth, and induction of erythroid differentiation were observed. The ras mutant, pZIPRas61leu-transfected cells, K562-Ras61leu, have shown a markedly decreased cell proliferation rate with approximately 2-fold doubling time, compared with the parental K562 cells, and about 60% of these cells have shown the phenotype of erythroid differentiation. In addition, herbimycin A inhibited the growth rate and increased the erythroid differentiation, but did not affect the elevated activity of ERK/MAPK in the K562-Ras61leu cells. On the other hand, effects of PD98059 on the growth and differentiation of K562-Ras61leu cells were biphasic. At low concentration of PD98059, which inhibited the elevated activity of ERK/MAPK to the level of parental cells, the growth rate increased and the erythroid differentiation decreased slightly, and at high concentration of PD98059, which inhibited the elevated activity of ERK/MAPK below that of the parental cells, the growth rate turned down and the erythroid differentiation was restored to the untreated control level. Taken together, these results suggest that an appropriate activity of ERK/MAPK is required to maintain the rapid growth and transformed phenotype of K562 cells.
携带Bcr-Abl酪氨酸激酶的慢性粒细胞白血病K562细胞系被认为是表达红系、粒系、单核系和巨核系谱系标志物的多能造血祖细胞。在此，我们研究了诱导K562细胞红系分化所需的信号调节。当用赫比霉素A（一种蛋白酪氨酸激酶抑制剂）、ras反义寡核苷酸和PD98059（MEK的特异性抑制剂）处理K562细胞时，观察到ERK/MAPK活性和细胞生长受到抑制，以及红系分化被诱导。ras突变体pZIPRas61leu转染的细胞K562-Ras61leu与亲代K562细胞相比，细胞增殖率明显降低，倍增时间约为2倍，并且这些细胞中约60%表现出红系分化表型。此外，赫比霉素A抑制了生长速率并增加了红系分化，但不影响K562-Ras61leu细胞中升高的ERK/MAPK活性。另一方面，PD98059对K562-Ras61leu细胞生长和分化的影响是双相的。在低浓度的PD98059下，其将升高的ERK/MAPK活性抑制到亲代细胞水平，生长速率增加且红系分化略有降低，而在高浓度的PD98059下，其将升高的ERK/MAPK活性抑制到低于亲代细胞水平，生长速率下降且红系分化恢复到未处理的对照水平。综上所述，这些结果表明ERK/MAPK的适当活性是维持K562细胞快速生长和转化表型所必需的。
