JNK and ERK signaling pathways in multistage mouse carcinogenesis: studies in the inhibition of signaling cascades as a means to understand their in vivo biological role.
Amplification and mutation of Ha-ras has been shown to correlate with the malignancy of tumors that appear in chemically-induced mouse skin. Cell lines isolated from mouse skin tumors represent the evolutionary stages of tumor development. Due to the high Ha-ras levels the JNK and ERK modules are found elevated, contributing to the enhanced AP-1 activity in the more malignant cells. To examine the role of the transforming Ha-ras in controlling ERK signaling, transfection of an activated Ha-ras allele was tested in a squamous cell carcinoma cell line. The ERK1/2 signaling pathways were blocked pharmacologically by PD98059 MEK inhibitor, which inhibited cell proliferation and anchorage-independent growth of squamous and spindle carcinoma cells. In addition, treatment with PD98059 and introduction of the dominant negative ATF-2 mutant into the spindle carcinoma cells, partially reverted the spindle phenotype to squamous-like. These results suggest that ERK1/2 and A TF-2 play an important role in oncogenicity and in the degree of progression within the mouse skin carcinogenesis system.
Katsanakis
Kostas D
KD
Institute of Biological Research and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
Owen
Carolyn
C
Zoumpourlis
Vassilis
V
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012878:Skin Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000235:genetics; D014162:Transfection
D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases