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The hyposensitive N187D P2X7 mutant promotes malignant progression in nude mice.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2010 Nov 12; Vol. 285 (46), pp. 36179-87. Date of Electronic Publication: 2010 Sep 13. - Publication Year :
- 2010
-
Abstract
- Nucleotides are new players in the intercellular communication network. P2X7 is a member of the P2X family of receptors, which are ATP-gated plasma membrane ion channels with diverse biological functions. Abnormal expression and dysfunction of P2X7 have been reported in leukemias. Here, we report a new P2X7 mutant (an A(559)-to-G substitution causing N187D P2X7) cloned from J6-1 leukemia cells. The characteristics of N187D P2X7 were studied by establishing stably transfected K562 cell lines. Our results show that N187D P2X7 required a higher concentration of agonist for its activation, leading to Ca(2+) influx (EC(50) = 293.3 ± 6.6 μm for the mutant and 93.6 ± 2.2 μm for wild-type P2X7) and ERK phosphorylation, which were not caused by differential cell-surface expression or related to high ATPase activity on the cell surface and in the extracellular space. K562 cells expressing this N187D mutant showed a proliferative advantage and reduced pro-apoptosis effects in vitro and in vivo. Furthermore, elevated angiogenesis and CD206-positive macrophage infiltration were found in tumor tissues formed by K562-M cells. In addition, higher expression of VEGF and MCP1 could be detected in tumor tissues formed by K562-M cells. Our results suggest that N187D P2X7, representing mutants hyposensitive to agonist, might be a positive regulator in the progression of hematopoietic malignancies.
- Subjects :
- Adenosine Triphosphate analogs & derivatives
Adenosine Triphosphate pharmacology
Animals
Blotting, Western
Calcium metabolism
Cell Line, Tumor
Disease Progression
Enzyme Activation drug effects
Female
Humans
Intracellular Space drug effects
Intracellular Space metabolism
K562 Cells
Leukemia, Experimental metabolism
Leukemia, Experimental pathology
MAP Kinase Signaling System drug effects
Macrophages metabolism
Macrophages pathology
Mice
Mice, Inbred BALB C
Mice, Nude
Neovascularization, Pathologic genetics
Neovascularization, Pathologic metabolism
Neovascularization, Pathologic pathology
Receptors, Purinergic P2X7 metabolism
Reverse Transcriptase Polymerase Chain Reaction
Transplantation, Heterologous
Tumor Burden genetics
p38 Mitogen-Activated Protein Kinases metabolism
Gene Expression Regulation, Leukemic
Leukemia, Experimental genetics
Mutation, Missense
Receptors, Purinergic P2X7 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 285
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20837475
- Full Text :
- https://doi.org/10.1074/jbc.M110.128488