The transcriptional repressor hDaxx potentiates p53-dependent apoptosis.
p53 and its homologues p73 and p63 are transcription factors that play an essential role in modulating cell cycle arrest and cell death in response to several environmental stresses. The type and intensity of these responses, which can be different depending on the inducing stimulus and on the overall cellular context, are believed to rely on the activation of defined subsets of target genes. The proper activation of p53 family members requires the coordinated action of post-translational modifications and interaction with several cofactors. In this study, we demonstrate that the multifunctional protein hDaxx interacts with p53 and its homologues, both in vitro and in vivo, and modulates their transcriptional activity. Moreover, we show that hDaxx, which has been implicated in several apoptotic pathways, increases the sensitivity to DNA damage-induced cell death and that this effect requires the presence of p53. Although hDaxx represses p53-dependent transcription of the p21 gene, it does not affect the activation of proapoptotic genes, and therefore acts by influencing the balance between cell cycle arrest and proapoptotic p53 targets. Our results therefore underline the central role of hDaxx in modulating the apoptotic threshold upon several stimuli and identify it as a possible integrating factor that coordinates the response of p53 family members.
Gostissa
Monica
M
Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Padriciano 99, 34012, Trieste, Italy.
Morelli
Manuela
M
Mantovani
Fiamma
F
Guida
Elisa
E
Piazza
Silvano
S
Collavin
Licio
L
Brancolini
Claudio
C
Schneider
Claudio
C
Del Sal
Giannino
G
D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D056970:Co-Repressor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques
D048868:Adaptor Proteins, Signal Transducing; C493956:CDKN1A protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D056970:Co-Repressor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; C106985:DAXX protein, human; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C115051:TP63 protein, human; C000606460:TP73 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins