p73-alpha is capable of inducing scotin and ER stress.
p73, like its family member p53, can induce programmed cell death following DNA damage. Here, we report that this mechanism also involves endoplasmic reticulum (ER) stress and the transactivation of scotin, a protein identified recently as a p53 target able to induce ER stress. By using Tet-On inducible cell lines (Saos 2 osteosarcoma cells that lack p53), we observed that TAp73alpha elicits significant alterations in the morphology of the ER system, namely in the fine subcellular localization of calnexin. We found that both TAp73alpha and p53 are strong inducers of scotin. On the other hand, the transcriptionally deficient short isoforms DeltaNp73alpha did not upregulate the steady-state mRNA level of scotin, as evaluated by real-time RT-PCR. Following the induction of scotin, ER staining with calnexin showed evidence of morphological alteration, with variations in the intracellular concentration of free calcium, visualized by fluo-3 staining. The induction of ER stress by p73 was further supported by the transcriptional induction of Gadd 153, a transcription factor induced under ER stress conditions. In conclusion, the data reported indicate the ability of TAp73alpha and p53 (not DeltaNp73alpha) to elicit scotin transactivation and ER stress. This molecular mechanism might contribute to the effector events inducing apoptosis downstream of p73.
Terrinoni
Alessandro
A
Biochemistry Laboratory, IDI-IRCCS, Department of Experimental Medicine and Biochemical Sciences, University of Rome 'Tor Vergata', 00133 Rome, Italy.
Ranalli
Marco
M
Cadot
Bruno
B
Leta
Aida
A
Bagetta
Giacinto
G
Vousden
Karen H
KH
Melino
Gerry
G
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D009687:Nuclear Proteins / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; C462779:SHISA5 protein, human; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins