Document Detail

Mitogen-activated protein kinase plays an essential role in the erythropoietin-dependent proliferation of CTLL-2 cells.
MedLine Citation:
PMID:  10960479     Owner:  NLM     Status:  MEDLINE    
Erythropoietin (EPO) and its receptor (EPOR) are required for development of erythrocytes. It has been shown that the ectopic expression of EPOR confers EPO-dependent proliferation on an interleukin 3 (IL3)-dependent cell line, Ba/F3, whereas the IL2-dependent T cell line, CTLL-2 expressing the EPOR (T-ER), fails to proliferate in response to EPO. However, the molecular basis of the EPO unresponsiveness in CTLL-2 has not been clarified. We found that the expression level of JAK2 in T-ER cells was much lower than that in Ba/F3 cells. Therefore, we examined the effects of forced expression of JAK2 in T-ER cells. In T-ER transformants expressing JAK2 (T-JER), EPO induced tyrosine phosphorylation of the EPOR, JAK2, and STAT5, and consequently STAT5-responsive genes including bcl-X and cis1 were normally induced. Furthermore, T-JER cells were resistant to apoptosis until at least 72 h after switching from IL2 to EPO. Although T-JER cells could not continuously proliferate in the presence of EPO, additional expression of JAK2 in T-JER (T-JJER) to a level similar to that in Ba/F3 cells supported long term proliferation in response to EPO. JAK2 was equally co-immunoprecipitated with the EPOR among T-JER, T-JJER, and Ba/F3 cells expressing the EPOR (BF-ER). However, EPO-dependent mitogen-activated protein (MAP) kinase activation was observed in T-JJER and BF-ER cells but not in T-JER cells. EPO-dependent long term proliferation of T-JER cells was conferred by expression of the constitutively activated form of MEK1. Our results suggest that MAP kinase activation is, at least in part, an important component for mitotic signal from the EPOR, and CTLL-2 cells probably lack signaling molecule(s) in JAK2 and the Ras-MAP kinase pathway.
H Sakamoto; T Kitamura; A Yoshimura
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  275     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2000 Nov 
Date Detail:
Created Date:  2000-12-29     Completed Date:  2000-12-29     Revised Date:  2012-06-05    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  35857-62     Citation Subset:  IM    
Institute of Life Science, Kurume University, Aikawa-machi 2432-3, Kurume 839-0861, Japan.
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MeSH Terms
Apoptosis / drug effects
Cell Division / drug effects
Cell Line
DNA-Binding Proteins / metabolism
Enzyme Activation / drug effects
Erythropoietin / pharmacology*
Gene Expression Regulation / drug effects
Interleukin-2 / pharmacology
Janus Kinase 2
MAP Kinase Kinase 1
Milk Proteins*
Mitogen-Activated Protein Kinase Kinases / metabolism
Mitogen-Activated Protein Kinases / metabolism*
Precipitin Tests
Protein-Serine-Threonine Kinases / metabolism
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins*
RNA, Messenger / genetics,  metabolism
Receptors, Erythropoietin / genetics,  metabolism
STAT5 Transcription Factor
Signal Transduction / drug effects
T-Lymphocytes, Cytotoxic / cytology*,  drug effects*,  enzymology,  metabolism
Trans-Activators / metabolism
Reg. No./Substance:
0/DNA-Binding Proteins; 0/Interleukin-2; 0/Milk Proteins; 0/Proto-Oncogene Proteins; 0/RNA, Messenger; 0/Receptors, Erythropoietin; 0/STAT5 Transcription Factor; 0/Trans-Activators; 11096-26-7/Erythropoietin; EC 2.7.1.-/MAP2K1 protein, human; EC 2.7.1.-/Map2k1 protein, mouse; EC Kinase 2; EC Kinases; EC protein, human; EC protein, mouse; EC Kinases; EC Protein Kinases; EC Kinase Kinase 1; EC Protein Kinase Kinases

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