Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line
Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line
复制标题
DOI：
10.1053/jhep.2001.20676
复制
发表时间：
2001-01-01
期刊：
影响因子：
13.5
通讯作者：
Patel, T
中科院分区：
文献类型：
--
作者：
Tadlock, L;Patel, T
虽然丝裂原活化蛋白激酶（MAPK）途径在细胞生长中起着关键作用，但它们在介导转化细胞生长表型改变中的作用仍不清楚。p44/p42 MAPK信号级联被人胆管细胞的促有丝分裂刺激激活。相反，p38 MAPK通路被恶性而非非恶性胆管细胞的有丝分裂原刺激激活。因此，我们的目的是确定p38 MAPK信号转导在介导转化胆管细胞生长表型中的作用。KMCH-1恶性人胆管细胞需要血清的存在下增殖，但能够在减少血清的条件下生长。抑制p38 MAPK可降低KMCH-1细胞的血清依赖性增殖，抑制p38 MAPK可降低KMCH-1细胞的贴壁非依赖性生长，而抑制p44/p42 MAPK则无此作用。虽然p38和p44/p42 MAPK都被有丝分裂原激活，但它们对锚定非依赖性生长的影响不同。抑制p38 MAPK而非p44/p42 MAPK信号通路可降低细胞周期进程并增加细胞周期蛋白依赖性激酶抑制剂p21（WAF 1/CIP 1）的表达。然而，p27（KIP 1）或p16（INK 4A）的表达不受这两种途径的影响。因此，有丝分裂原激活p38 MAPK降低p21（WAF 1/CIP 1）的表达，并介导生长独立的锚定信号，而有丝分裂原激活p44/p42 MAPK介导的锚定信号依赖性的生长途径。这些数据提供了异常应激激活的细胞信号传导与转化细胞的改变的生长表型之间的联系，这对于开发限制转化细胞生长的疗法可能是重要的。
Although mitogen-activated protein kinase (MAPK) pathways play a key role in cell growth, their role in mediating the altered growth phenotype of transformed cells remains unclear. The p44/p42 MAPK signaling cascades are activated by mitogenic stimulation of human cholangiocytes. In contrast, the p38 MAPK pathway is activated by mitogen stimulation of malignant, but not nonmalignant cholangiocytes, Thus, our aims were to determine the role of p38 MAPK signaling in mediating the growth phenotype of transformed cholangiocytes. KMCH-1 malignant human cholangiocytes required the presence of serum for proliferation, but were able to grow in reduced serum conditions. Inhibition of p38 MAPK decreased serum-dependent proliferation of KMCH-1 cells, Furthermore, inhibition of p38 MAPK, but not of p44/p42 MAPK, reduced anchorage-independent growth of KMCH-1 cells. Although both p38 and p44/p42 MAPK are activated in response to mitogens, they have divergent effects on anchorage-independent growth. Inhibition of p38 MAPK, but not of p44/p42 MAPK signaling, decreased cell cycle progression and increased expression of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) However, expression of p27(KIP1) Or p16(INK4A) was not altered by either pathway. Thus, mitogen activation of p38 MAPK decreases expression of p21(WAF1/CIP1) and mediates growth independent of anchorage signals, whereas mitogen activation of p44/p42 MAPK mediates an anchorage signal-dependent growth pathway. These data provide a link between aberrant stress-activated cell signaling and the altered growth phenotype of transformed cells that may be important for the development of therapies to limit transformed cell growth.