Puma and p53 play required roles in death evoked in a cellular model of Parkinson disease.
6-Hydroxydopamine (6-OHDA) is widely used in vivo and in vitro to mimic the selective neuronal degeneration that characterizes Parkinson disease (PD). To uncover candidate genes that may mediate neuron death in PD, we previously used SAGE to identify transcripts that are rapidly induced by 6-OHDA in neuronally differentiated PC12 cells. Among induced pro-apoptotic genes was that encoding the BH3-only protein PUMA. Here, we confirm that 6-OHDA induces both PUMA mRNA and protein. 6-OHDA additionally induced Bim, another pro-apoptotic BH3-only protein. Using specific siRNAs, we demonstrate that PUMA, but not Bim, is required for death evoked by 6-OHDA. PUMA is a target of p53, a transcription factor activated by 6-OHDA. Involvement of p53 in 6-OHDA evoked death was confirmed by the protective actions of a DN p53 and pifithrin alpha, inhibitors of p53 signaling. Our findings thus indicate that p53 and PUMA play required roles in a cellular model of PD.
Biswas
Subhas C
SC
Department of Pathology, Center for Neurobiology and Behavior and Taub Center for Alzheimer's Disease Research, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. scb34@columbia.edu
Ryu
Elizabeth
E
Park
Clara
C
Malagelada
Cristina
C
Greene
Lloyd A
LA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D001483:Base Sequence; D017931:DNA Primers; D006801:Humans; D009419:Nerve Tissue Proteins / Q000502:physiology*; D016627:Oxidopamine / Q000494:pharmacology; D016716:PC12 Cells; D010300:Parkinson Disease / Q000473:pathology* / Q000503:physiopathology; D034741:RNA, Small Interfering; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D017931:DNA Primers; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D016627:Oxidopamine