The midblastula transition in Xenopus embryos activates multiple pathways to prevent apoptosis in response to DNA damage.
Apoptosis is controlled by a complex interplay between regulatory proteins. Previous work has shown that Xenopus embryos remove damaged cells by apoptosis when irradiated before, but not after, the midblastula transition (MBT). Here we demonstrate that Akt/protein kinase B is activated and mediates an antiapoptotic signal only in embryos irradiated after the MBT. In addition, an increase in xBcl-2/xBax oligomerization and a decrease in xBax homodimerization promote a protective effect against apoptosis only after the MBT. The post-MBT survival mechanism arrests cells in G(1) phase by increasing expression of the cyclin-dependent kinase inhibitor p27(Xic1). p27(Xic1) associates with cyclin D/Cdk4 and cyclin A/Cdk2 complexes to cause G(1)/S arrest, perhaps allowing more time for DNA repair. Taken together, the results define the DNA damage response as an element of the MBT and indicate that multiple mechanisms prevent apoptosis after the MBT.
Finkielstein
C V
CV
Howard Hughes Medical Institute and Department of Pharmacology, University of Colorado School of Medicine, Denver, CO 80262, USA.
Lewellyn
A L
AL
Maller
J L
JL
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001755:Blastocyst / Q000166:cytology* / Q000502:physiology* / Q000528:radiation effects; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000502:physiology* / Q000528:radiation effects; D018797:Cell Cycle Proteins; D056741:Cyclin D; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000502:physiology; D016193:G1 Phase; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D009024:Morphogenesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016196:S Phase; D025521:Tumor Suppressor Proteins; D014981:Xenopus / Q000196:embryology*; D029867:Xenopus Proteins
D018797:Cell Cycle Proteins; D056741:Cyclin D; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D029867:Xenopus Proteins; C493963:Xicl protein, Xenopus; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D042846:CDC2-CDC28 Kinases; C495891:Cdk2 protein, Xenopus; C495899:Cdk4 protein, Xenopus; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases