The involvement of diadenosine 5',5"'-P1,P4-tetraphosphate in cell cycle arrest and regulation of apoptosis.
Diadenosine oligophosphates (Ap(n)A) have been proposed to function as intracellular and extracellular signaling molecules in animal cells. Here, we have examined the cellular and molecular mechanisms underlying the induction of apoptosis by diadenosine 5',5"'-P(1),P(4)-tetraphosphate (Ap(4)A). We have shown a dose-dependent apoptotic response in cells treated with Ap(4)A. Flow cytometric analysis indicated an involvement of Ap(4)A at an early stage of G1/S arrest. No difference in the amount of p21(waf1) was observed in HL60 cells treated with Ap(4)A compared to control cells. The level of retinoblastoma protein (pRb) dropped dramatically when apoptosis was extensive. The cleavage of pRb was abrogated if Ap(4)A-treated cells were incubated with general caspase inhibitor zVAD-fmk. Ap(4)A also induced a profound decrease in the level of the Bcl-2 protein. The lack of effect of Ap(4)A on CDK1 activity indicated that Ap(4)A is not involved in "aberrant mitosis". We suggest that in vivo Ap(4)A may play a significant role in tumor growth suppression by inducing apoptosis.
Vartanian
Amalia A
AA
Engelhardt Institute of Molecular Biology, Vavilova 32, 119991 Moscow, Russia. vartan@imb.ac.ru
Suzuki
H
H
Poletaev
Andrey I
AI
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D004347:Drug Interactions; D016193:G1 Phase / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000494:pharmacology; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase / Q000187:drug effects*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D015226:Dinucleoside Phosphates; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; C020733:diadenosine tetraphosphate; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases