Intracellular GTP level determines cell's fate toward differentiation and apoptosis
Since the adequate supply of guanine nucleotides is vital for cellular activities, limitation of their syntheses would certainly result in modulation of cellular fate toward differentiation and apoptosis. The aim of this study was to set a correlation between the intracellular level of GTP and the induction of relevant signaling pathways involved in the cell's fate toward life or death. In that regard, we measured the GTP level among human leukemia K562 cells exposed to mycophenolic acid (MPA) or 3-hydrogenkwadaphnin (3-HK) as two potent inosine monophosphate dehydrogenase inhibitors. Our results supported the maturation of the cells when the intracellular GTP level was reduced by almost 30-40%. Under these conditions, 3-HK and/or MPA caused up-regulation of PKC{alpha} and PI3K/AKT pathways. Furthermore, co-treatment of cells with hypoxanthine plus 3-HK or MPA, which caused a reduction of about 60% in the intracellular GTP levels, led to apoptosis and activation of mitochondrial pathways through inverse regulation of Bcl-2/Bax expression and activation of caspase-3. Moreover, our results demonstrated that attenuation of GTP by almost 60% augmented the intracellular ROS and nuclear localization of p21 and subsequently led to cell death. These results suggest that two different threshold levels of GTP are needed for induction of differentiation and/or ROS-associated apoptosis. - Graphical abstract: Display Omitted
- OSTI ID:
- 21587769
- Journal Information:
- Toxicology and Applied Pharmacology, Vol. 253, Issue 3; Other Information: DOI: 10.1016/j.taap.2011.02.021; PII: S0041-008X(11)00075-5; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
- Country of Publication:
- United States
- Language:
- English
Similar Records
5-AIQ inhibits H{sub 2}O{sub 2}-induced apoptosis through reactive oxygen species scavenging and Akt/GSK-3β signaling pathway in H9c2 cardiomyocytes
Isoorientin induces apoptosis through mitochondrial dysfunction and inhibition of PI3K/Akt signaling pathway in HepG2 cancer cells
Related Subjects
ADENOSINE
APOPTOSIS
ATP
DMSO
GLYCOPROTEINS
GUANINE
GUANOSINE
HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY
HYPOXANTHINE
INOSINE
LEUKEMIA
PHOSPHATES
SYNTHESIS
AMINES
AROMATICS
AZAARENES
CARBOHYDRATES
CHROMATOGRAPHY
DISEASES
HETEROCYCLIC COMPOUNDS
HYDROXY COMPOUNDS
IMMUNE SYSTEM DISEASES
LIQUID COLUMN CHROMATOGRAPHY
NEOPLASMS
NUCLEOSIDES
NUCLEOTIDES
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANIC SULFUR COMPOUNDS
OXYGEN COMPOUNDS
PHOSPHORUS COMPOUNDS
PROTEINS
PURINES
RIBOSIDES
SACCHARIDES
SEPARATION PROCESSES
SULFOXIDES