PDCD5 interacts with p53 and functions as a positive regulator in the p53 pathway
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ORIGINAL PAPER
PDCD5 interacts with p53 and functions as a positive regulator in the p53 pathway Lanjun Xu • Jing Hu • Yuanbo Zhao Jia Hu • Juan Xiao • Yanming Wang Dalong Ma • Yingyu Chen
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Published online: 23 August 2012 Ó Springer Science+Business Media, LLC 2012
Abstract The tumor suppressor p53 is at the hub of cellular signaling networks that are activated by stress signals including DNA damage. In the present study, we showed that programmed cell death 5 (PDCD5) bound to p53 by glutathione S-transferase (GST)-pulldown, co-immunoprecipitation and co-localization assays. PDCD5 enhanced the stability of p53 by antagonizing Mdm2-induced p53 ubiquitination, nuclear export and proteasomal degradation. We also found that PDCD5 could dissociate the interaction between p53 and Mdm2 and interact with Mdm2 directly to promote its degradation. In cells with or without induction of DNA damage, knockdown of PDCD5 by RNA interference decreased the p53 phosphorylation at Ser9, 20 and 392 residues, as well as the expression of p21 protein. Additionally, chromatin immunoprecipitation assays showed an up-regulated association of PDCD5 at the p53BS2 site of the p21 promoter during DNA damage. Cell cycle analysis also indicated that PDCD5 was required in G1 phase cell arrest during DNA damage. In summary, PDCD5 may contribute to maintain a basal pool of p53 proteins in unstressed conditions, but upon DNA damage it functions as a co-activator of p53 to regulate transcription and cell cycle arrest.
L. Xu Y. Zhao J. Hu J. Xiao D. Ma Y. Chen (&) Key Laboratory of Medical Immunology, Ministry of Health, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China e-mail: [email protected] L. Xu Y. Zhao J. Hu J. Xiao D. Ma Y. Chen Peking University Center for Human Disease Genomics, 38 Xueyuan Road, Beijing 100191, China J. Hu Y. Wang Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA
Keywords
PDCD5 p53 Mdm2 p21 Cell cycle
Introduction The tumor suppressor p53 is a powerful transcriptional factor and plays a central role in the regulation of cell cycle, DNA repair, apoptosis, senescence and angiogenesis. As a sequence-specific transcription factor, p53 mainly functions by inducing transcription of many different downstream genes, including genes involved in cell cycle arrest, such as p21/WAF1/CIP1 and GADD45, as well as those inducing apoptosis, such as PUMA, Bax and PIG3 [1–3]. However, p53 can also control apoptosis through transcription-independent mechanisms [4]. Under normal conditions, p53 is maintained at a low level by interacting with E3 ubiquitin ligases such as Mdm2 [5], Pirh2 [6], COP1 [7] and ARF-BP1 [8], which mediate p53 degradation by the ubiquitin–proteasome pathway. However, under stressed conditions, such as DNA damage, p53 is stabilized and activated to function primarily as a transcription factor and regulating expression of downstream target genes. This leads to different cellular outcomes
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