PMID- 12609835
OWN - NLM
STAT- MEDLINE
DCOM- 20040204
LR  - 20211203
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 101
IP  - 12
DP  - 2003 Jun 15
TI  - Induction of apoptosis in IL-3-dependent hematopoietic cell lines by guanine 
      nucleotide depletion.
PG  - 4958-65
AB  - Inosine 5'-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that 
      catalyzes the conversion of IMP to xanthosine monophosphate (XMP) at the branch 
      point of purine nucleotide biosynthesis, leading to the generation of guanine 
      nucleotides. Inhibition of IMPDH results in the depletion of guanine nucleotides, 
      prevents cell growth by G1 arrest, and induces cell differentiation in a 
      cell-type-specific manner. The molecular and sensing mechanisms underlying these 
      effects are not clear. We have examined the induction of apoptosis by 
      mycophenolic acid (MPA), a specific IMPDH inhibitor, in interleukin-3 
      (IL-3)-dependent murine hematopoietic cell lines. MPA treatment, at clinically 
      relevant doses, caused apoptosis in 32D myeloid cells and in FL5.12 and BaF3 
      pre-B cells in the ongoing presence of IL-3. Apoptosis was completely prevented 
      by the addition of guanosine at time points up to 12 hours, after which caspase 3 
      activity increased and apoptosis was not reversible. MPA treatment caused marked 
      down-regulation of the MAP kinase kinase/extracellular regulatory kinase 
      (MEK/Erk) pathway at 3 hours while simultaneously increasing the phosphorylation 
      of c-Jun kinase. In addition, MPA strongly down-regulated the mammalian target of 
      rapamcyin (mTOR) pathway, as indicated by the decreased phosphorylation of p70 S6 
      kinase and of 4EBP1. Inhibition of either the mitogen-activated protein kinase 
      (MAPK) or the mTOR pathway alone by standard pharmacologic inhibitors did not 
      induce apoptosis in IL-3-dependent cells, whereas inhibition of both pathways 
      simulated the effects of MPA treatment. These results indicate that IMPDH 
      inhibitors may be effective in modulating signal transduction pathways in 
      hematopoietic cells, suggesting their usefulness in chemotherapeutic regimens for 
      hematologic malignancies.
FAU - Gu, Jing Jin
AU  - Gu JJ
AD  - Lineberger Comprehensive Cancer Center, Department of Pharmacology, University of 
      North Carolina at Chapel Hill, 27599, USA.
FAU - Gathy, Karen
AU  - Gathy K
FAU - Santiago, Lalaine
AU  - Santiago L
FAU - Chen, Eric
AU  - Chen E
FAU - Huang, Min
AU  - Huang M
FAU - Graves, Lee M
AU  - Graves LM
FAU - Mitchell, Beverly S
AU  - Mitchell BS
LA  - eng
GR  - CA 64193/CA/NCI NIH HHS/United States
GR  - GM-59767/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20030227
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Guanine Nucleotides)
RN  - 0 (Interleukin-3)
RN  - 0 (Milk Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (STAT3 Transcription Factor)
RN  - 0 (STAT5 Transcription Factor)
RN  - 0 (Stat3 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 12133JR80S (Guanosine)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 1.1.1.205 (IMP Dehydrogenase)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.4.22.- (Casp3 protein, mouse)
RN  - EC 3.4.22.- (Caspase 3)
RN  - EC 3.4.22.- (Caspases)
RN  - HU9DX48N0T (Mycophenolic Acid)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects
MH  - Caspase 3
MH  - Caspases/metabolism
MH  - Cell Line
MH  - DNA-Binding Proteins/metabolism
MH  - Enzyme Inhibitors/pharmacology
MH  - Guanine Nucleotides/deficiency/*physiology
MH  - Guanosine/pharmacology
MH  - Guanosine Triphosphate/metabolism
MH  - Hematopoietic Stem Cells/*cytology
MH  - IMP Dehydrogenase/antagonists & inhibitors
MH  - Interleukin-3/*pharmacology
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Mice
MH  - *Milk Proteins
MH  - Mitogen-Activated Protein Kinase Kinases/metabolism
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Mycophenolic Acid/pharmacology
MH  - Phosphorylation
MH  - Protein Kinases/metabolism
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - STAT3 Transcription Factor
MH  - STAT5 Transcription Factor
MH  - Signal Transduction
MH  - Sirolimus/metabolism
MH  - TOR Serine-Threonine Kinases
MH  - Trans-Activators/metabolism
EDAT- 2003/03/01 04:00
MHDA- 2004/02/05 05:00
CRDT- 2003/03/01 04:00
PHST- 2003/03/01 04:00 [pubmed]
PHST- 2004/02/05 05:00 [medline]
PHST- 2003/03/01 04:00 [entrez]
AID - S0006-4971(20)50665-4 [pii]
AID - 10.1182/blood-2002-08-2547 [doi]
PST - ppublish
SO  - Blood. 2003 Jun 15;101(12):4958-65. doi: 10.1182/blood-2002-08-2547. Epub 2003 
      Feb 27.