PMID- 8993834
OWN - NLM
STAT- MEDLINE
DCOM- 19970523
LR  - 20131121
IS  - 1044-9523 (Print)
IS  - 1044-9523 (Linking)
VI  - 8
IP  - 1
DP  - 1997 Jan
TI  - A decrease in the intracellular guanosine 5'-triphosphate concentration is 
      necessary for granulocytic differentiation of HL-60 cells, but growth cessation 
      and differentiation are not associated with a change in the activation state of 
      Ras, the transforming principle of HL-60 cells.
PG  - 53-9
AB  - We found that when human promyelocytic leukemic cells (HL-60 cells) were induced 
      to differentiate along the granulocytic lineage by two diverse mechanisms 
      (starvation for an essential amino acid or treatment with DMSO), there was a 
      marked decrease in the intracellular guanosine 5'-triphosphate (GTP) 
      concentration with no change in the guanosine 5'-diphosphate (GDP) concentration. 
      Differentiation was prevented by guanine or guanosine in a dose-dependent manner. 
      We showed that: (a) guanine had to be converted to a nucleotide because it did 
      not prevent differentiation of hypoxanthine-guanine 
      phosphoribosyltransferase-deficient HL-60 cells; (b) the effect of guanine 
      correlated with a return of the cytosolic GTP:GDP ratio to normal; and (c) other 
      purine bases were not effective. We hypothesized that the decreased GTP:GDP ratio 
      in differentiating HL-60 cells might decrease the relative amount of GTP bound to 
      Ras, a key regulatory GTP-binding protein important to cell growth and 
      differentiation. Consistent with data showing that HL-60 cells harbor an 
      activating N-Ras mutation, we found that the percentage of Ras molecules in the 
      GTP-bound state was high in proliferating HL-60 cells (27 +/- 3%) compared with 
      other cultured mammalian cells (< 1%); however, we found no change in the 
      activation state of Ras when cells ceased to proliferate and differentiated in 
      response to DMSO, amino acid deprivation, or inhibitors of guanylate synthesis. 
      We conclude that: (a) a decrease in the intracellular GTP concentration is 
      necessary for HL-60 cells to undergo granulocytic differentiation; and (b) 
      although a high degree of Ras activation contributes to the malignant phenotype 
      of the cell, there is no change in the activation state of Ras during 
      granulocytic differentiation.
FAU - Pilz, R B
AU  - Pilz RB
AD  - Department of Medicine, University of California, San Diego, La Jolla 92093-0652, 
      USA.
FAU - Huvar, I
AU  - Huvar I
FAU - Scheele, J S
AU  - Scheele JS
FAU - Van den Berghe, G
AU  - Van den Berghe G
FAU - Boss, G R
AU  - Boss GR
LA  - eng
GR  - CA01548/CA/NCI NIH HHS/United States
GR  - GM49360/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.
PL  - United States
TA  - Cell Growth Differ
JT  - Cell growth & differentiation : the molecular biology journal of the American 
      Association for Cancer Research
JID - 9100024
RN  - 0 (Amino Acids)
RN  - 146-91-8 (Guanosine Diphosphate)
RN  - 5Z93L87A1R (Guanine)
RN  - 86-01-1 (Guanosine Triphosphate)
RN  - EC 1.1.1.205 (IMP Dehydrogenase)
RN  - EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - YOW8V9698H (Dimethyl Sulfoxide)
SB  - IM
MH  - Amino Acids/deficiency
MH  - Cell Differentiation/drug effects/*physiology
MH  - Cell Division/drug effects/*physiology
MH  - Dimethyl Sulfoxide/pharmacology
MH  - Guanine/pharmacology
MH  - Guanosine Diphosphate/metabolism
MH  - Guanosine Triphosphate/*metabolism
MH  - HL-60 Cells/drug effects/*metabolism
MH  - Humans
MH  - Hypoxanthine Phosphoribosyltransferase/deficiency
MH  - IMP Dehydrogenase/antagonists & inhibitors
MH  - ras Proteins/*metabolism
EDAT- 1997/01/01 00:00
MHDA- 1997/01/01 00:01
CRDT- 1997/01/01 00:00
PHST- 1997/01/01 00:00 [pubmed]
PHST- 1997/01/01 00:01 [medline]
PHST- 1997/01/01 00:00 [entrez]
PST - ppublish
SO  - Cell Growth Differ. 1997 Jan;8(1):53-9.