title: Positive feedback regulation of p53 transactivity by DNA damage-induced ISG15 modification.
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.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Jong Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Yang
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Jung Mi
authors.initials: JM
authors.lastname: Park
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Seung Hyeun
authors.initials: SH
authors.lastname: Ka
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Young-Yun
authors.initials: YY
authors.lastname: Kong
authors.affiliation: Department of Biochemistry, Institute of Medical Science, Chungnam National University School of Medicine, Daejon 34134, Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Jeon
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Seol
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 08826, Korea.|The 2nd Division of Natural Sciences, National Academy of Science, Seoul 06579, Korea.
authors.forename: Chin Ha
authors.initials: CH
authors.lastname: Chung
mesh_terms: D000107:Acetylation; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D004317:Doxorubicin / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics* / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D051028:bcl-2-Associated X Protein; C074034:ISG15 protein, human; D004317:Doxorubicin; C471622:UBE2L6 protein, human; D044763:Ubiquitin-Conjugating Enzymes; C534879:UBA7 protein, human; D044764:Ubiquitin-Activating Enzymes