title: Identification of flotillin-2, a major protein on lipid rafts, as a novel target of p53 family members.
abstract: p73 and p63 are members of the p53 gene family and have been shown to play an important role in development and homeostasis mainly by regulating the transcription of a variety of genes. A subset of these genes encodes secreted proteins and receptors that may be involved in the communication between adjacent cells. We report here that flotillin-2, a major hydrophobic protein on biomembrane microdomain lipid rafts, is a direct transcriptional target of the p53 family member genes. It has been suggested that such rafts could play an important role in many cellular processes including signal transduction, membrane trafficking, cytoskeletal organization, and pathogen entry. We found that the expression of flotillin-2 was specifically up-regulated by either TAp73beta or TAp63gamma, but not significantly by p53. In addition, flotillin-2 transcription is activated in response to cisplatin in a manner dependent on endogenous p73. By using small interference RNA designed to target p73, we showed that silencing endogenous p73 abolishes the induction of flotillin-2 transcription following cisplatin treatment. Furthermore, we identified a p73/p63-binding site located upstream of the flotillin-2 gene that is responsive to the p53 family members. This response element is highly conserved between humans and rodents. We also found that ectopic expression of TAp73 as well as TAp63 enhances signal transduction by assessing the interleukin-6-mediated phosphorylation of signal transducers and activators of transcription 3. Thus, in addition to direct transactivation, p53 family member genes enhance a set of cellular processes via lipid rafts.
authors.affiliation: Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University, Chuo-ku, Sapporo, 060-8556 Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Oshima
authors.forename: Ryota
authors.initials: R
authors.lastname: Koyama
authors.forename: Reo
authors.initials: R
authors.lastname: Maruyama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Akashi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mita
authors.forename: Minoru
authors.initials: M
authors.lastname: Toyota
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Takashi
authors.initials: T
authors.lastname: Tokino
mesh_terms: D015152:Blotting, Northern; D045744:Cell Line, Tumor; D017931:DNA Primers; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D015850:Interleukin-6; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016159:Tumor Suppressor Protein p53; C106354:flotillins