Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells.
Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells.
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DOI：
10.1101/gad.14.5.574
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发表时间：
2000-03
影响因子：
10.5
通讯作者：
P. L. Puri;Zhenguo Wu;Peilin Zhang;L. Wood;K. Bhakta;Jiahuai Han;J. Feramisco;M. Karin;Jean Y. J.
中科院分区：
文献类型：
--
作者：
P. L. Puri;Zhenguo Wu;Peilin Zhang;L. Wood;K. Bhakta;Jiahuai Han;J. Feramisco;M. Karin;Jean Y. J.
MyoD抑制细胞增殖并促进肌肉分化。横纹肌肉瘤（RMS）是一种由肌肉前体细胞引起的肿瘤，其一个矛盾的特征是尽管MyoD表达，但分化程序和增殖失调却被阻断。先前的研究表明，MyoD活性所需的一个因子RMS存在缺陷。我们在这里报告，p38 MAP激酶（MAPK）的激活，这是必不可少的肌肉分化，是缺乏RMS细胞。通过活化的MAPK激酶6（MKK6EE）对p38 MAPK的强制诱导恢复了MyoD功能并增强了p38 MAPK活化缺陷的RMS中的MEF2活性，导致生长停滞和终末分化。应激和细胞因子可激活RMS细胞p38 MAPK，但这些刺激并不促进RMS细胞的分化，可能是因为应激和细胞因子仅短暂激活p38 MAPK，同时激活JNK，而JNK可拮抗RMS细胞的分化。因此，选择性和持续的p38 MAPK激活，这是不同于应激激活的反应，是分化所需的，并可以在人类肿瘤中被破坏。
MyoD inhibits cell proliferation and promotes muscle differentiation. A paradoxical feature of rhabdomyosarcoma (RMS), a tumor arising from muscle precursors, is the block of the differentiation program and the deregulated proliferation despite MyoD expression. A deficiency in RMS of a factor required for MyoD activity has been implicated by previous studies. We report here that p38 MAP kinase (MAPK) activation, which is essential for muscle differentiation, is deficient in RMS cells. Enforced induction of p38 MAPK by an activated MAPK kinase 6 (MKK6EE) restored MyoD function and enhanced MEF2 activity in RMS deficient for p38 MAPK activation, leading to growth arrest and terminal differentiation. Stress and cytokines could activate the p38 MAPK in RMS cells, however, these stimuli did not promote differentiation, possibly because they activated p38 MAPK only transiently and they also activated JNK, which could antagonize differentiation. Thus, the selective and sustained p38 MAPK activation, which is distinct from the stress-activated response, is required for differentiation and can be disrupted in human tumors.