Activation of the Jun N-terminal kinase pathway by friend spleen focus-forming virus and its role in the growth and survival of friend virus-induced erythroleukemia cells.
Members of the mitogen-activated protein kinase (MAPK) family, including Jun amino-terminal kinase (JNK) and extracellular signal-related kinase (ERK), play an important role in the proliferation of erythroid cells in response to erythropoietin (Epo). Erythroid cells infected with the Friend spleen focus-forming virus (SFFV) proliferate in the absence of Epo and show constitutive activation of Epo signal transduction pathways. We previously demonstrated that the ERK pathway was constitutively activated in Friend SFFV-infected erythroid cells, and in this study JNK is also shown to be constitutively activated. Pharmacological inhibitors of both the ERK and JNK pathways stopped the proliferation of primary erythroleukemic cells from Friend SFFV-infected mice, with little induction of apoptosis, and furthermore blocked their ability to form Epo-independent colonies. However, only the JNK inhibitor blocked the proliferation of erythroleukemia cell lines derived from these mice. The JNK inhibitor caused significant apoptosis in these cell lines as well as an increase in the fraction of cells in G(2)/M and undergoing endoreduplication. In contrast, the growth of erythroleukemia cell lines derived from Friend murine leukemia virus (MuLV)-infected mice was inhibited by both the MEK and JNK inhibitors. JNK is important for AP1 activity, and we found that JNK inhibitor treatment reduced AP1 DNA-binding activity in primary erythroleukemic splenocytes from Friend SFFV-infected mice and in erythroleukemia cell lines from Friend MuLV-infected mice but did not alter AP1 DNA binding in erythroleukemia cell lines from Friend SFFV-infected mice. These data suggest that JNK plays an important role in cell proliferation and/or the survival of erythroleukemia cells.
Nishigaki
Kazuo
K
Laboratory of Cancer Prevention, National Cancer Institute--Frederick, MD 21702-1201, USA.
Hanson
Charlotte
C
Thompson
Delores
D
Yugawa
Takashi
T
Ruscetti
Sandra
S
D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002461:Cell Line, Transformed / Q000821:virology; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D004921:Erythropoietin; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D012192:Retroviridae Infections / Q000378:metabolism*; D015398:Signal Transduction; D013155:Spleen Focus-Forming Viruses / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000502:physiology; D014412:Tumor Virus Infections / Q000378:metabolism*
D000873:Anthracenes; D005419:Flavonoids; D018808:Transcription Factor AP-1; D004921:Erythropoietin; C432165:pyrazolanthrone; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one