p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress.
Cells respond 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.
Cuenin
S
S
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Tinel
A
A
Janssens
S
S
Tschopp
J
J
D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D053143:Caspase 2 / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics; D053418:Death Domain Receptor Signaling Adaptor Proteins; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D016328:NF-kappa B; C485896:PIDD1 protein, human; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D053143:Caspase 2