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The Journal of Neuroscience, November 7, 2007, 27(45):12198-12210; doi:10.1523/JNEUROSCI.3222-05.2007
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Cellular/Molecular
Apoptotic Actions of p53 Require Transcriptional Activation of PUMA and Do Not Involve a Direct Mitochondrial/Cytoplasmic Site of Action in Postnatal Cortical Neurons
Takuma Uo, Yoshito Kinoshita, andRichard S. Morrison Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington 98195-6470
Correspondence should be addressed to Dr. Richard S. Morrison, Department of Neurological Surgery, University of Washington School of Medicine, Box 356470, Seattle, WA 98195-6470. Email: yael{at}u.washington.edu
Recent studies in non-neuronal cells have shown that the tumor suppressor p53 can promote cell death through a transcription-independent mechanism involving its direct action with a subset of Bcl-2 family member proteins in the cytosol and at the mitochondria. In cultured cortical neurons, however, we could not find evidence supporting a significant contribution of the cytosolic/mitochondrial p53 pathway, and available evidence instead corroborated the requirement for the transcriptional activity of p53. When directly targeted to the cytosol/mitochondria, wild-type p53 lost its apoptosis-inducing activity in neurons but not in non-neuronal cells. The N-terminal p53 fragment (transactivation and proline-rich domains), which induces apoptosis in non-neuronal cells via the cytosolic/mitochondrial pathway, displayed no apoptogenic activity in neurons. In neuronal apoptosis induced by camptothecin or an MDM2 (murine double minute 2) inhibitor, nutlin-3, endogenous p53 protein did not accumulate in the cytosol/mitochondria, and transcriptional inhibition after p53 induction effectively blocked cell death. In addition, overexpression of a dominant-negative form of p53 (R273H) completely suppressed induction of proapoptotic p53 target genes and cell death. PUMA (p53-upregulated modulator of apoptosis) was one such gene induced by camptothecin, and its overexpression was sufficient to induce Bax (Bcl-2-associated X protein)-dependent neuronal death, whereas Noxa was not apoptogenic. These results collectively demonstrate that, in contrast to non-neuronal cells, the apoptotic activity of p53 in postnatal cortical neurons does not rely on its direct action at the cytosol/mitochondria but is exclusively mediated through its transcription-dependent functions. The uniqueness of p53-mediated apoptotic signaling in postnatal cortical neurons was further illustrated by the dispensable function of the proline-rich domain of p53.
Key words: apoptosis; caspases; p53; mitochondria; transcription; neuronal cell death
Received Aug. 2, 2005; revised Sept. 5, 2007; accepted Sept. 5, 2007.
Correspondence should be addressed to Dr. Richard S. Morrison, Department of Neurological Surgery, University of Washington School of Medicine, Box 356470, Seattle, WA 98195-6470. Email: yael{at}u.washington.edu
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