Mechanism of induction of apoptosis by p73 and its relevance to neuroblastoma biology.
TP73, as a TP53 homologue, drew the attention of tumor biologists because it is rarely mutated in human cancers and can induce cell cycle arrest and apoptosis by activating genes also regulated by p53. However, TP73 harbors an additional promoter that produces a dominant negative p73 protein (deltaNp73) having the opposite effect of the TAp73 protein. Thus, the regulation of p53 responsive genes in the absence of p53 relies on a critical balance between different p73 gene-derived proteins. Recent reports have described additional complexity in the mechanism of action of transcriptionally active p73 (TAp73) in the induction of cell death. The molecular mechanism through which p73 induces apoptosis involves (i) expression and changes in subcellular localization of scotin, producing an endoplasmic reticulum (ER) stress; and (ii) transactivation of PUMA and Bax, thus determining cell fate. On the contrary, deltaNp73 inhibits apoptosis, thus contributing to the oncogenic potential of neuroblastoma cells.
Rossi
Mario
M
Medical Research Council Toxicology Unit, Leicester, United Kingdom.
Sayan
A Emre
AE
Terrinoni
Alessandro
A
Melino
Gerry
G
Knight
Richard A
RA
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D016923:Cell Death; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008565:Membrane Proteins; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000378:metabolism; D009447:Neuroblastoma / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology*; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D019253:Proto-Oncogene Proteins c-bcl-2; C462779:SHISA5 protein, human; C000606460:TP73 protein, human; D014157:Transcription Factors; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051028:bcl-2-Associated X Protein; C000606369:delta Np73 protein, human