Partial depletion of intracellular ATP mediates the stress-survival function of the PCPH oncoprotein.
Promotion of cellular resistance to stressful stimuli, including ionizing radiation and chemotherapeutic drugs, contributes to the transforming activity of the PCPH oncogene. The mechanism of this action, however, has remained unknown. Consistent with its intrinsic ATP diphosphohydrolase activity, expression of the PCPH oncoprotein in cultured cells has now been shown to result in partial depletion of intracellular ATP and consequent inhibition of the c-JUN NH2-terminal kinase-mediated stress signaling pathway. Supplementation of cells expressing the PCPH oncoprotein with exogenous ATP restored both stress-response signaling and sensitivity to cisplatin-induced apoptosis. In contrast, overexpression of the wild-type PCPH protein had a minimal effect on stress-induced signaling and on the cellular ATP content and did not protect cells from apoptosis. These results suggest that the PCPH oncoprotein confers resistance to stressors by reducing the cellular ATP concentration to levels below those required for optimal stress-induced signaling and apoptosis. Treatment with adenosine or nucleoside analogues may thus enhance the response to radiation or chemotherapy of tumors that express the PCPH oncogene.
Recio
Juán A
JA
Laboratory of Experimental Carcinogenesis, Department of Radiation Medicine, Georgetown University Medical Center, Washington, DC 20007, USA.
Páez
J Guillermo
JG
Sanders
Sean
S
Kawakami
Toshiaki
T
Notario
Vicente
V
D016475:3T3 Cells; D000255:Adenosine Triphosphate / Q000172:deficiency* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D004789:Enzyme Activation; D005656:Fungal Proteins; D050980:GATA Transcription Factors; D048728:MAP Kinase Kinase Kinase 1; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015513:Oncogene Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis / Q000235:genetics; D013312:Stress, Physiological / Q000201:enzymology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D015533:Transcriptional Activation / Q000502:physiology; D014162:Transfection
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D050980:GATA Transcription Factors; D015513:Oncogene Proteins; C485537:Pcph protein, mouse; D016760:Proto-Oncogene Proteins c-fos; C115209:Sre protein, Neurospora crassa; D018808:Transcription Factor AP-1; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse