Promoter specificity and stability control of the p53-related protein p73.
The p53 family of proteins play instrumental roles in mediating the cellular response to stress. The p53-related gene product, p73, occurs as two distinct protein isoforms, referred to as alpha and beta, which differ in the length of the C-terminal region and arise through alternative splicing of the p73 RNA. Here, we describe an analysis of the transcription properties of p73 and show that although there are certain similarities between transcriptional activation mediated by p73 and p53, such as in their sensitivity to adenovirus E1A and the requirement for p300/CBP co-activator proteins, significant differences are apparent in the response mechanisms. Thus, we find that p73 shows a degree of specificity for the promoters of target genes that is quantitatively distinct from the response mediated by p53. For example, p73 activates the GADD45 gene more efficiently than p53, whereas the reverse situation was apparent for the p21 gene. These effects are, in part, due to the influence of a regulatory domain present in the extended C-terminal of the alpha isoform. Moreover, we provide evidence that this domain regulates protein abundance by influencing the proteasome-dependent degradation of p73. These data define a novel level of isoform-specific control in regulating p73 activity, and thereby highlight a significant difference between the mechanisms that govern the transcriptional activity of p53 and p73.
Lee
C W
CW
Division of Biochemistry and Molecular Biology, University of Glasgow, UK.
La Thangue
N B
NB
D017500:Adenovirus E1A Proteins / Q000235:genetics / Q000378:metabolism; D001859:Bone Neoplasms / Q000473:pathology; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D003609:Dactinomycin / Q000494:pharmacology; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D016147:Genes, Tumor Suppressor; D016259:Genes, myc; D016158:Genes, p53; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D005810:Multigene Family; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D012516:Osteosarcoma / Q000473:pathology; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms / Q000235:genetics* / Q000502:physiology; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012326:RNA Splicing; D011993:Recombinant Fusion Proteins / Q000502:physiology; D017384:Sequence Deletion; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins
D017500:Adenovirus E1A Proteins; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins; D003609:Dactinomycin; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019384:Nucleic Acid Synthesis Inhibitors; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms; D011506:Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D016283:Proto-Oncogene Proteins p21(ras); D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000097642:GADD45 Proteins; C000606460:TP73 protein, human; C497206:MDM2 protein, human; C501009:HRAS protein, human