Protein kinase C regulates mitochondrial targeting of Nur77 and its family member Nor-1 in thymocytes undergoing apoptosis.
Nur77 orphan steroid receptor and its family member Nor-1 are required for apoptosis of developing T cells. In thymocytes, signals from the TCR complex induce Nur77 and Nor-1 expression followed by translocation from the nucleus to mitochondria. Nur77 and Nor-1 associate with Bcl-2 in the mitochondria, resulting in a conformation change that exposes the Bcl-2 BH3 domain, a presumed pro-apoptotic molecule of Bcl-2. As Nur77 and Nor-1 are heavily phosphorylated, we examined the requirement of Nur77 and Nor-1 phosphorylation in mitochondria translocation and Bcl-2 BH3 exposure. We found that HK434, a PKC agonist, in combination with calcium ionophore, can induce Nur77 and Nor-1 phosphorylation, translocation, Bcl-2 BH3 exposure and thymocyte apoptosis. Inhibitors of both classical and novel forms of PKC were able to block this process. In contrast, only the general but not classical PKC-specific inhibitors were able to block the same process initiated by PMA, a commonly used PKC agonist. These data demonstrate a differential activation of PKC isoforms by PMA and HK434 in thymocytes, and show the importance of PKC in mitochondria translocation of Nur77/Nor-1 and Bcl-2 conformation change during TCR-induced thymocyte apoptosis.
Thompson
Jennifer
J
Cancer Research Laboratory and Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, CA, USA.
Burger
Megan L
ML
Whang
Hannah
H
Winoto
Astar
A
D021581:Active Transport, Cell Nucleus; D000494:Allosteric Regulation; D017209:Apoptosis / Q000276:immunology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics / Q000378:metabolism*; D057106:Nuclear Receptor Subfamily 4, Group A, Member 3 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013950:Thymus Gland / Q000473:pathology
D051023:BH3 Interacting Domain Death Agonist Protein; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D057106:Nuclear Receptor Subfamily 4, Group A, Member 3; D019253:Proto-Oncogene Proteins c-bcl-2; D011948:Receptors, Antigen, T-Cell; D011493:Protein Kinase C
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