Abstract
p53 plays a pivotal role in tumour suppression under stresses, such as DNA damage. ISG15 has been implicated in the control of tumorigenesis. Intriguingly, the expression of ISG15, UBE1L and UBCH8 is induced by DNA-damaging agents, such as ultraviolet and doxorubicin, which are known to induce p53. Here, we show that the genes encoding ISG15, UBE1L, UBCH8 and EFP, have the p53-responsive elements and their expression is induced in a p53-dependent fashion under DNA damage conditions. Furthermore, DNA damage induces ISG15 conjugation to p53 and this modification markedly enhances the binding of p53 to the promoters of its target genes (for example, CDKN1 and BAX) as well as of its own gene by promoting phosphorylation and acetylation, leading to suppression of cell growth and tumorigenesis. These findings establish a novel feedback circuit between p53 and ISG15-conjugating system for positive regulation of the tumour suppressive function of p53 under DNA damage conditions.
Highlights
P53 plays a pivotal role in tumour suppression under stresses, such as DNA damage
ChIP analysis revealed that overexpressed p53 in p53 À / À HCT116 cells effectively binds to each of the identified p53-responsive element (p53RE) of the genes, as it does to p53RE of the p21 gene (Supplementary Fig. 6). These results indicate that the promotor regions of the ISG15, UBE1L, UBCH8 and EFP genes have p53REs and their expressions are positively regulated by p53
In the present study, we showed that the promoters of the ISG15, UBE1L, UBCH8 and EFP genes have p53REs for their p53-mediated expression, independent of type-I IFNs
Summary
The genes encoding ISG15-conjugating system has p53REs. We examined whether the genes encoding ISG15-conjugating system have the p53-response elements (p53REs) for their p53-mediated expression. Of note was the finding that knockdown of ISG15 or EFP results in a significant reduction in p53 expression (see Figs 4b and 5c), raising a possibility that p53 ISGylation might be involved in the control of its transactivity, in addition its stability, and thereby in the expression of its target genes (including its own) To test this possibility, p53 and its ISGylation-defective 2KR mutant were expressed in p53-null H1299 cells that had been transfected with p53-responsive reporter vectors, including PG13-Luc, p21-Luc and BAX-Luc. The 2KR mutation caused a marked decrease in ultraviolet-induced p53 transactivity (Fig. 6a). TUNEL assay revealed that apoptosis is markedly reduced in cells expressing 2KR mutant compared with those expressing wild-type p53 (Supplementary Fig. 17) These results indicate that DNA damage-induced ISGylation of p53 promotes cell growth inhibition and apoptosis by increasing its transactivity. It remains unknown how the belated expression of UBP43 is regulated under DNA damage conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
