title: L-GILZ binds p53 and MDM2 and suppresses tumor growth through p53 activation in human cancer cells.
abstract: The transcription factor p53 regulates the expression of genes crucial for biological processes such as cell proliferation, metabolism, cell repair, senescence and apoptosis. Activation of p53 also suppresses neoplastic transformations, thereby inhibiting the growth of mutated and/or damaged cells. p53-binding proteins, such as mouse double minute 2 homolog (MDM2), inhibit p53 activation and thus regulate p53-mediated stress responses. Here, we found that long glucocorticoid-induced leucine zipper (L-GILZ), a recently identified isoform of GILZ, activates p53 and that the overexpression of L-GILZ in p53(+/+) HCT116 human colorectal carcinoma cells suppresses the growth of xenografts in mice. In the presence of both p53 and MDM2, L-GILZ binds preferentially to MDM2 and interferes with p53/MDM2 complex formation, making p53 available for downstream gene activation. Consistent with this finding, L-GILZ induced p21 and p53 upregulated modulator of apoptosis (PUMA) expression only in p53(+/+) cells, while L-GILZ silencing reversed the anti-proliferative activity of dexamethasone as well as expression of p53, p21 and PUMA. Furthermore, L-GILZ stabilizes p53 proteins by decreasing p53 ubiquitination and increasing MDM2 ubiquitination. These findings reveal L-GILZ as a regulator of p53 and a candidate for new therapeutic anti-cancer strategies for tumors associated with p53 deregulation.
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Ayroldi
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Petrillo
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Bastianelli
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Marchetti
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ronchetti
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Nocentini
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ricciotti
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Cannarile
authors.affiliation: Department Medicine, Section of Pharmacology, University of Perugia Medical School, Perugia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D055550:Protein Stability; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C498608:Dsip1 protein, mouse; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; C404226:TSC22D3 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2