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Cancer Genes and Genomics

Identification of Flotillin-2, a Major Protein on Lipid Rafts, as a Novel Target of p53 Family Members

¹ Department of Molecular Biology, Cancer Research Institute, ² First Department of Internal Medicine, and ³ Department of Informatic Science, Sapporo Medical University, Chuo-ku, Sapporo, Japan

Requests for reprints: Takashi Tokino, Department of Molecular Biology, Cancer Research Institute, Sapporo Medical University. S-1, W-17, Chuo-ku, Sapporo, 060-8556 Japan. Phone: 81-11-611-2111, ext. 2410; Fax: 81-11-618-3313. E-mail: tokino{at}sapmed.ac.jp

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 TAp73β or TAp63, 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. (Mol Cancer Res 2008;6(3):395–406)