Required roles of Bax and JNKs in central and peripheral nervous system death of retinoblastoma-deficient mice.
Retinoblastoma-deficient mice show massive neuronal damage and deficits in both CNS and PNS tissue. Previous work in the field has shown that death is regulated through distinct processes where CNS tissue undergoes death regulated by the tumor suppressor p53 and the apoptosome component, APAF1. Death in the PNS, however, is independent of p53 and reliant on the death protease, caspase 3. In the present study, we more carefully delineated the common and distinct mechanisms of death regulation by examining the stress-activated kinases, JNK2 and 3, the conserved Bcl-2 member Bax, and the relationship among these elements including p53. By use of genetic modeling, we show that death in various regions of the CNS and DRGs of the PNS is reliant on Bax. In the CNS, Bax acts downstream of p53. The relevance of the JNKs is more complex, however. Surprisingly, JNK3 deficiency by itself does not inhibit c-Jun phosphorylation and instead, aggravates death in both CNS and PNS tissue. However, JNK2/3 double deficiency blocks death due to Rb loss in both the PNS and CNS. Importantly, the relationships between JNKs, p53, and Bax exhibit regional differences. In the medulla region of the hindbrain in the CNS, JNK2/3 deficiency blocks p53 activation. Moreover, Bax deficiency does not affect c-Jun phosphorylation. This indicates that a JNK-p53-Bax pathway is central in the hindbrain. However, in the diencephalon regions of the forebrain (thalamus), Bax deficiency blocks c-Jun activation, indicating that a Bax-JNK pathway of death is more relevant. In the DRGs of the PNS, a third pathway is present. In this case, a JNK-Bax pathway, independent of p53, regulates damage. Accordingly, our results show that a death regulator Bax is common to death in both PNS and CNS tissue. However, it is regulated by or itself regulates different effectors including the JNKs and p53 depending upon the specific region of the nervous system.
Keramaris
Elizabeth
E
Department of Cellular Molecular Medicine, Neuroscience East, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the.
Ruzhynsky
Vladamir A
VA
Department of Cellular Molecular Medicine, Neuroscience East, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the.
Callaghan
Steve M
SM
Department of Cellular Molecular Medicine, Neuroscience East, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the.
Wong
Estelle
E
Department of Cellular Molecular Medicine, Neuroscience East, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the.
Davis
Roger J
RJ
Department of Biochemistry and Molecular Biology, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
Flavell
Richard
R
Section of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520.
Slack
Ruth S
RS
Department of Cellular Molecular Medicine, Neuroscience East, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the.
Park
David S
DS
Department of Cellular Molecular Medicine, Neuroscience East, Ottawa Health Research Institute, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada, the. Electronic address: dpark@uottawa.ca.
D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000502:physiology; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005838:Genotype; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017933:Peripheral Nervous System / Q000166:cytology / Q000378:metabolism*; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D048031:JNK Mitogen-Activated Protein Kinases