Upon intracellular processing, the C-terminal death domain-containing fragment of the p53-inducible PIDD/LRDD protein translocates to the nucleoli and interacts with nucleolin

Pick, Robert; Badura, Susanne; Bösser, Susanne; Zörnig, Martin

doi:10.1016/j.bbrc.2006.08.176

Cited by 22 publications

(23 citation statements)

References 25 publications

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“…We have recently shown that PIDD isoform 1 is autoprocessed at S446 and S588 to generate a PIDD-C and a PIDD-CC fragment (Tinel et al, 2007), in agreement with previous reports (Telliez et al, 2000;Pick et al, 2006). The 11 amino-acid deletion in isoform 2 encompasses the second cleavage site used for PIDD The two C terminal fragments generated by PIDD autoprocessing have distinct functions (Tinel et al, 2007).…”

Section: Pidd Isoforms 1 2 and 3 Activate Nf-kbsupporting

confidence: 90%

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

et al. 2007

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Cellsres pond to DNA damage in a complex way and the fate of damaged cells depends on the balance between pro-and antiapoptotic signals. This is of crucial importance in cancer as genotoxic stress is implied both in oncogenesis and in classical tumor therapies. p53-induced protein with a death domain (PIDD), initially described as a p53-inducible gene, is one of the molecular switches able to activate a survival or apoptotic program. Two isoforms of PIDD, PIDD ( isoform 1) and LRDD ( isoform 2), have already been reported and we describe here a third isoform. These three isoforms are differentially expressed in tissues and cell lines. Genotoxic stress only affects PIDD isoform 3 mRNA levels, whereas isoforms 1 and 2 mRNA levels remain unchanged. All isoforms are capable of activating nuclear factor-kappaB in response to genotoxic stress, but only isoform 1 interacts with RIP-associated ICH-1/CED-3 homologous protein with a death domain and activates caspase-2. Isoform 2 counteracts the pro-apoptotic function of isoform 1, whereas isoform 3 enhances it. Thus, the differential splicing of PIDD mRNA leads to the formation of at least three proteins with antagonizing/agonizing functions, thereby regulating cell fate in response to DNA damage

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Section: Pidd Isoforms 1 2 and 3 Activate Nf-kbsupporting

confidence: 90%

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

et al. 2007

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“…In agreement with previous studies on the stability of Hsp90 clients, 16,18 PIDD degradation in response to GA also occurs in a mainly proteasome-dependent manner, as shown by the inhibitory effect of MG132 ( Figure 2c, lane 4,5 versus 8,9). Although over time PIDD degradation is also detected in the presence of MG132 (Figure 2c, lane [6][7][8][9]. Previously demonstrated with c-erbB-2, for example, 20 Hsp90 substrates are often ubiquitinated in response to GA preceding their degradation, which, as shown in Figure 2d, is also the case for PIDD.…”

supporting

confidence: 68%

“…In unstimulated cells, both active fragments of PIDD can be readily detected because of constitutive auto-processing of the full-length protein, 6,8,9 but no activation of NF-kB or caspase-2 can be observed. In order to understand the mechanism of how PIDD activity is regulated, we screened for potential novel PIDD regulators and found many representatives of the molecular chaperone machinery.…”

mentioning

confidence: 99%

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90

et al. 2010

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In response to DNA damage, p53-induced protein with a death domain (PIDD) forms a complex called the PIDDosome, which either consists of PIDD, RIP-associated protein with a death domain and caspase-2, forming a platform for the activation of caspase-2, or contains PIDD, RIP1 and NEMO, important for NF-jB activation. PIDDosome activation is dependent on autoprocessing of PIDD at two different sites, generating the fragments PIDD-C and PIDD-CC. Despite constitutive cleavage, endogenous PIDD remains inactive. In this study, we screened for novel PIDD regulators and identified heat shock protein 90 (Hsp90) as a major effector in both PIDD protein maturation and activation. Hsp90, together with p23, binds PIDD and inhibition of Hsp90 activity with geldanamycin efficiently disrupts this association and impairs PIDD auto-processing. Consequently, both PIDD-mediated NF-jB and caspase-2 activation are abrogated. Interestingly, PIDDosome formation itself is associated with Hsp90 release. Characterisation of cytoplasmic and nuclear pools of PIDD showed that active PIDD accumulates in the nucleus and that only cytoplasmic PIDD is bound to Hsp90. Finally, heat shock induces Hsp90 release from PIDD and PIDD nuclear translocation. Thus, Hsp90 has a major role in controlling PIDD functional activity.

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“…(B) qRT-PCR validation of the ATM-and p53-dependent response for 13 IR-induced genes. (26), and thus may function as an adaptor protein in cell death-related signaling processes; PHLDA3, which encodes a repressor of Akt, a major prosurvival kinase (27); the genes encoding the F-box proteins FBXO22 and FBXW7, subunits of SCF ubiquitin ligase complexes; RNF19B, encoding an E3 ubiquitin ligase; DCP1B, encoding an RNA decapping enzyme; and DDIT4, encoding an inhibitor of signaling associated with mammalian target of rapamycin (mTOR).…”

Section: Transcriptome Dynamics After X-irradiationmentioning

confidence: 99%

Parallel Profiling of the Transcriptome, Cistrome, and Epigenome in the Cellular Response to Ionizing Radiation

et al. 2014

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The DNA damage response (DDR) is a vast signaling network that is robustly activated by DNA double-strand breaks, the critical lesion induced by ionizing radiation (IR). Although much of this response operates at the protein level, a critical component of the network sustains many DDR branches by modulating the cellular transcriptome. Using deep sequencing, we delineated three layers in the transcriptional response to IR in human breast cancer cells: changes in the expression of genes encoding proteins or long noncoding RNAs, alterations in genomic binding by key transcription factors, and dynamics of epigenetic markers of active promoters and enhancers. We identified protein-coding and previously unidentified noncoding genes that were responsive to IR, and demonstrated that IR-induced transcriptional dynamics was mediated largely by the transcription factors p53 and nuclear factor κB (NF-κB) and was primarily dependent on the kinase ataxia-telangiectasia mutated (ATM). The resultant data set provides a rich resource for understanding a basic, underlying component of a critical cellular stress response.

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Upon intracellular processing, the C-terminal death domain-containing fragment of the p53-inducible PIDD/LRDD protein translocates to the nucleoli and interacts with nucleolin

Cited by 22 publications

References 25 publications

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress

Regulation of PIDD auto-proteolysis and activity by the molecular chaperone Hsp90

Parallel Profiling of the Transcriptome, Cistrome, and Epigenome in the Cellular Response to Ionizing Radiation

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