TY - JOUR
T1 - Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line
AU - Tadlock, Laura
AU - Patel, Tushar
N1 - Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2001
Y1 - 2001
N2 - 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 p4.4/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 MAPKsignaling, decreased cell cycle progression and increased expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. However, expression of p27KIP1 or p16INK4A was not altered by either pathway. Thus, mitogen activation of p38 MAPK decreases expression of p21WAF1/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.
AB - 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 p4.4/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 MAPKsignaling, decreased cell cycle progression and increased expression of the cyclin-dependent kinase inhibitor p21WAF1/CIP1. However, expression of p27KIP1 or p16INK4A was not altered by either pathway. Thus, mitogen activation of p38 MAPK decreases expression of p21WAF1/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.
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U2 - 10.1053/jhep.2001.20676
DO - 10.1053/jhep.2001.20676
M3 - Article
C2 - 11124819
AN - SCOPUS:0035192909
SN - 0270-9139
VL - 33
SP - 43
EP - 51
JO - Hepatology
JF - Hepatology
IS - 1
ER -