Hydroquinone modulates the GM-CSF signaling pathway in TF-1 cells.
Human leukemogens, including alkylating chemotherapeutic agents and benzene, enhance granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent proliferation of human CD34+ bone marrow (BM) cells. The extracellular signal-regulated kinase (ERK) pathway plays an important role in GM-CSF-dependent proliferation and also has been implicated in the pathogenesis of acute myelogenous leukemia. Therefore, we investigated the effects of the benzene metabolite, hydroquinone (HQ), on alterations in the GM-CSF signaling pathway in TF-1 erythroleukemia cells and human CD34+ BM cells. HQ treatment in TF-1 cells results in a strong proliferative response that is dependent on ERK activation and GM-CSF production. HQ also induces ERK-dependent AP-1 activation with concomitant increased transcriptional activity of AP-1 reporter gene. However, the kinetics of ERK activation are different between rhGM-CSF and HQ in TF-1 cells: rhGM-CSF results in immediate activation of ERK, whereas HQ activation of ERK is delayed. Further, HQ and rhGM-CSF together produce an immediate increase in ERK phosphorylation, which is sustained for over 48 h. HQ also stimulates colony formation, AP-1 DNA binding and GM-CSF production in human CD34+ BM cells. These results suggest that HQ stimulates proliferation via activation of ERK/AP-1 and is at least partially mediated via the production of GM-CSF.
Zheng
J H
JH
Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO, USA.
Pyatt
D W
DW
Gross
S A
SA
Le
A T
AT
Kerzic
P J
PJ
Irons
R D
RD
D018952:Antigens, CD34; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D007700:Kinetics; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology*; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D018952:Antigens, CD34; D002273:Carcinogens; D006873:Hydroquinones; D011994:Recombinant Proteins; D018808:Transcription Factor AP-1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020928:Mitogen-Activated Protein Kinases; C031927:hydroquinone