title: The RASSF3 candidate tumor suppressor induces apoptosis and G1-S cell-cycle arrest via p53.
abstract: RASSF3 is the smallest member of the RASSF family of proteins that function as tumor suppressors. Unlike other members of this important family, the mechanisms through which RASSF3 suppresses tumor formation remain unknown. Here, we show that RASSF3 expression induces p53-dependent apoptosis and its depletion attenuates DNA damage-induced apoptosis. We found that RASSF3-induced apoptosis depended upon p53 expression. Exogenous expression of RASSF3 induced G(1)-S arrest, which was also p53 dependent. In contrast, loss of RASSF3 promoted cell-cycle progression, abrogated UVB- and VP-16-induced G(1)-S arrest, decreased p53 protein and target gene expression, and prevented DNA repair. RASSF3 was shown to directly interact with and facilitate the ubiquitination of MDM2, the E3 ligase that targets p53 for degradation, thereby increasing p53 stabilization. Together, our findings show the tumor suppressor activity of RASSF3, which occurs through p53 stabilization and regulation of apoptosis and the cell cycle.
authors.affiliation: Department of Medical Biochemistry, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Kudo
authors.forename: Mitsunobu
authors.initials: M
authors.lastname: Ikeda
authors.forename: Misa
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Zeyu
authors.initials: Z
authors.lastname: Yang
authors.forename: Kikuo
authors.initials: K
authors.lastname: Ohno
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nakagawa
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hata
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology; D000595:Amino Acid Sequence; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D004260:DNA Repair; D016193:G1 Phase; D006801:Humans; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000502:physiology*; D011123:Polyploidy; D051736:Proto-Oncogene Proteins c-mdm2 / Q000502:physiology; D016196:S Phase; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C428449:MOAP1 protein, human; C454041:RASSF3 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D020559:Monomeric GTP-Binding Proteins