PMID- 8977235
OWN - NLM
STAT- MEDLINE
DCOM- 19970206
LR  - 20210218
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 88
IP  - 12
DP  - 1996 Dec 15
TI  - Multiple signaling pathways induced by granulocyte colony-stimulating factor 
      involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of 
      three distinct classes of immediate early genes.
PG  - 4435-44
AB  - Granulocyte colony-stimulating factor (G-CSF) is the major regulator of 
      proliferation and differentiation of neutrophilic granulocyte precursor cells. 
      G-CSF activates multiple signaling molecules, including the JAK1 and JAK2 kinases 
      and the STAT transcription factors. To investigate G-CSF signaling events 
      regulated by the JAK-STAT pathway, we have generated UT7-epo cells stably 
      expressing either wild-type (wt) G-CSF receptor or a series of C-terminal 
      deletion mutants. Gel mobility shift and immunoprecipitation/Western analysis 
      showed that STAT5 is rapidly activated by G-CSF in cells expressing the wt G-CSF 
      receptor, in addition to the previously reported STAT3 and STAT1. Mutants lacking 
      any tyrosine residues in the cytoplasmic domain maintain their ability to 
      activate STAT5 and STAT1 but cannot activate STAT3, implying that STAT5 and STAT1 
      activation does not require receptor tyrosine phosphorylation. We also observed 
      significant changes in the ratio of STAT1:STAT3:STAT5 activated by various G-CSF 
      receptor C-terminal deletion mutants. These mutant receptors were further used to 
      investigate the role of JAKs and STATs in G-CSF-mediated responses in these 
      cells. We found that JAK activation correlates with G-CSF-induced cell 
      proliferation, whereas STAT activation is not required. We have also identified 
      three classes of G-CSF immediate early genes, whose activation correlates with 
      the activation of distinct JAK-STAT pathways. Our data show that, whereas c-fos 
      is regulated through a pathway independent of STAT activation, oncostatin M, 
      IRF-1, and egr-1 are regulated by an STAT5-dependent pathway and fibrinogen is 
      regulated by an STAT3-dependent pathway. In conclusion, our results suggest that 
      G-CSF regulates its complex biologic activities by selectively activating 
      distinct early response genes through different JAK-STAT signaling molecules.
FAU - Tian, S S
AU  - Tian SS
AD  - Ligand Pharmaceuticals, San Diego, CA 92121, USA.
FAU - Tapley, P
AU  - Tapley P
FAU - Sincich, C
AU  - Sincich C
FAU - Stein, R B
AU  - Stein RB
FAU - Rosen, J
AU  - Rosen J
FAU - Lamb, P
AU  - Lamb P
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Milk Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT3 protein, human)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (Trans-Activators)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.2 (JAK3 protein, human)
RN  - EC 2.7.10.2 (Janus Kinase 3)
SB  - IM
MH  - Animals
MH  - Cell Division/genetics
MH  - Cell Line
MH  - DNA-Binding Proteins/*physiology
MH  - Enzyme Activation/physiology
MH  - Gene Expression Regulation
MH  - Genes, Immediate-Early/*genetics
MH  - Granulocyte Colony-Stimulating Factor/genetics/*pharmacology
MH  - Humans
MH  - Janus Kinase 3
MH  - *Milk Proteins
MH  - Mutation
MH  - Protein-Tyrosine Kinases/*metabolism
MH  - STAT3 Transcription Factor
MH  - STAT5 Transcription Factor
MH  - Signal Transduction/*drug effects/genetics
MH  - Trans-Activators/*physiology
EDAT- 1996/12/15 00:00
MHDA- 1996/12/15 00:01
CRDT- 1996/12/15 00:00
PHST- 1996/12/15 00:00 [pubmed]
PHST- 1996/12/15 00:01 [medline]
PHST- 1996/12/15 00:00 [entrez]
AID - S0006-4971(20)65003-0 [pii]
PST - ppublish
SO  - Blood. 1996 Dec 15;88(12):4435-44.