p73 induces apoptosis by different mechanisms.
p73, like its homologue, the tumor suppressor p53, is able to induce apoptosis in several cell types. This property is important for the involvement of p73 in cancer development and therapy. However, in contrast with p53, the TAp73 gene has two distinct promoters coding for two protein isoforms with opposite effects: while the transactivation proficient TAp73 shows pro-apoptotic effects, the amino-terminal-deleted DeltaNp73 has an anti-apoptotic function. Indeed, the relative expression of these two proteins is related to the prognosis of several cancers. Here we discuss recent developments in the control of p73-induced apoptosis. First, TAp73 induces ER stress via the direct transactivation of Scotin. Second, TAp73 induces the mitochondrial pathway by directly transactivating both Bax and the BH3 only protein PUMA promoters. While the first transactivation is weak, and not sufficient to trigger apoptosis (at least in the in vitro cellular models so far evaluated), the induction of PUMA is strong and lethal. Third, the promoter of the death receptor CD95 contains a p53 responsive element and preliminary experiments suggest that TAp73 also activates the death receptor pathway. In addition, TAp73 is able to transactivate its own second promoter, thus inducing the expression of the anti-apoptotic DeltaNp73 isoform. Therefore, the balance between TAp73 and DeltaNp73 finely regulates cellular sensitivity to death.
Ramadan
Saafa
S
Laboratory of Biochemistry and Molecular Biology, IRCCS-Fondazione Santa Lucia, Via Ardeatina 306, 00179 Rome, Italy.
Terrinoni
Alessandro
A
Catani
Maria Valeria
MV
Sayan
A Emre
AE
Knight
Richard A
RA
Mueller
Martina
M
Krammer
Peter H
PH
Melino
Gerry
G
Candi
Eleonora
E
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D004249:DNA Damage / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms / Q000096:biosynthesis / Q000502:physiology; D011506:Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000502:physiology; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D025521:Tumor Suppressor Proteins
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011506:Proteins; D011518:Proto-Oncogene Proteins; C462779:SHISA5 protein, human; C484209:TMBIM6 protein, human; C000606460:TP73 protein, human; D014157:Transcription Factors; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C000606369:delta Np73 protein, human; C454920:delta Np73, mouse