TAp63 is a transcriptional target of NF-kappaB.
The p53 homologue p63 encodes multiple protein isoforms either with (TA) or without (DeltaN) the N-terminal transactivation domain. Accumulating evidence indicates that TAp63 plays an important role in various biological processes, including cell proliferation, differentiation, and apoptosis. However, how TAp63 is regulated remains largely unclear. In this study, we demonstrate that NF-kappaB induces TAp63 gene expression. The responsible elements for NF-kappaB-mediated TAp63 induction are located within the region from -784 to -296 bp in the TAp63 promoter, which contains two NF-kappaB binding sites. Ectopic expression of RelA stimulates TAp63 promoter-driven reporter activity and increases endogenous TAp63 mRNA levels. Inhibition of NF-kappaB by IkappaBalpha super-repressor or with a chemical inhibitor leads to down regulation of TAp63 mRNA expression and activity. In addition, mutations in the critical NF-kappaB-binding sites significantly abolish the effects of NF-kappaB on TAp63. Activation of NF-kappaB by TNFalpha enhances p50/RelA binding to the NF-kappaB binding sites. Furthermore, we show that an Sp1 site adjacent to the NF-kappaB sites plays a role in NF-kappaB-mediated upregulation of TAp63. Taken together, these data reveal that TAp63 is a transcriptional target of NF-kappaB, which may play a role in cell proliferation, differentiation and survival upon NF-kappaB activation by various stimuli.
Wu
Junfeng
J
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Bergholz
Johann
J
Lu
Jinin
J
Sonenshein
Gail E
GE
Xiao
Zhi-Xiong Jim
ZX
D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D006801:Humans; D016328:NF-kappa B / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors; D015533:Transcriptional Activation; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
D016328:NF-kappa B; D012333:RNA, Messenger; D016329:Sp1 Transcription Factor; C115051:TP63 protein, human; D015534:Trans-Activators; D051996:Transcription Factor RelA; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins