title: Ribophorin II regulates breast tumor initiation and metastasis through the functional suppression of GSK3β.
abstract: Mutant p53 (mtp53) gain of function (GOF) contributes to various aspects of tumor progression including cancer stem cell (CSC) property acquisition. A key factor of GOF is stabilization and accumulation of mtp53. However, the precise molecular mechanism of the mtp53 oncogenic activity remains unclear. Here, we show that ribophorin II (RPN2) regulates CSC properties through the stabilization of mtp53 (R280K and del126-133) in breast cancer. RPN2 stabilized mtp53 by inactivation of glycogen synthase kinase-3β (GSK3β) which suppresses Snail, a master regulator of epithelial to mesenchymal transition. RPN2 knockdown promoted GSK3β-mediated suppression of heat shock proteins that are essential for mtp53 stabilization. Furthermore, our study reveals that high expression of RPN2 and concomitant accumulation of mtp53 were associated with cancer tissues in a small cohort of metastatic breast cancer patients. These findings elucidate a molecular mechanism for mtp53 stabilization and suggest that RPN2 could be a promising target for anti-CSC therapy.
authors: Division of Molecular and Cellular Medicine, 1-1, Tsukiji 5-chome, Chuo-ku, Tokyo 104-0045, Japan.
authors: Ryou-u
authors: RU
authors: Takahashi
authors: Fumitaka
authors: F
authors: Takeshita
authors: Kimi
authors: K
authors: Honma
authors: Masaya
authors: M
authors: Ono
authors: Kikuya
authors: K
authors: Kato
authors: Takahiro
authors: T
authors: Ochiya
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000556:secondary*; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C034241:ribophorin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
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